KR101851728B1 - A modified taurine compound and a method of producing thereof - Google Patents

Abstract

The present invention relates to a modified taurine and a method for producing the modified taurine, and more particularly to a modified taurine having a different atomic distance between a conventional taurine and a sulfur (S) linked to an intramolecular carbon (C), and a method for producing the same.
The modified taurine of the present invention is expected to be widely used in the medical field because it has excellent effects for the prevention and treatment of metabolic diseases.

Description

[0001] The present invention relates to modified taurine and a method for producing the same,

The present invention relates to a modified taurine and a method for producing the same, and more particularly, to a modified taurine having a different atomic distance between a conventional taurine and a sulfur (S) linked to a carbon in a molecule (C), and a process for producing the same.

Obesity is a disease caused by excessive body fat accumulation due to unbalance of body energy consumption and consumption. It is necessary to prepare countermeasures because it affects mental health as well as physical diseases such as cardiovascular disease, diabetes, hypertension, hyperlipidemia and cholelithiasis (Kopelman PG, Obesity as medical problem., Nature 404: 635-643, 2000). Obesity management is especially important for Asians, because their body mass index is at least abdominal obesity higher than that of Westerners, and they are highly susceptible to complications caused by arterial diseases such as hypertension, diabetes and hyperlipidemia.

Obesity, about 30-40% of modern people, is known to be a strong risk factor for hypertension, coronary artery disease, type 2 diabetes and various types of cancer. The risk of developing obesity in obesity is four times higher in hypertensive patients and 10 times higher in diabetic patients than in normal people, and obesity and diabetes are particularly closely related to the disease mechanism.

In addition, obesity and diabetes as well as thrombotic diseases are becoming serious problems of metabolic diseases. Therefore, there is a demand for development of a substance that can prevent or treat metabolic diseases such as obesity, diabetes, and thrombotic diseases more effectively.

On the other hand, taurine is a type of amino acid, which is a food, which is hardly contained in plants. However, taurine is widely distributed in animals and exhibits an inhibitory action on sympathetic nerves in the brain to help stabilize blood pressure and prevent stroke, , Low density lipoprotein (LDL) cholesterol which causes angina pectoris, myocardial infarction and the like, and is known to be effective for various diseases such as vascular diseases and dementia as well as platelet aggregation action in blood vessels.

However, taurine is difficult to make a useful modification or composition having therapeutic ability for various diseases, and generally taurine is used as a raw material in an amino acid food state.

Accordingly, the present inventors have made intensive efforts to develop a modified taurine having different atomic distances of sulfur (S) linked to taurine and intramolecular carbon (C). The modified taurine of the present invention is expected to be widely used in the medical field because it has excellent effects for the prevention and treatment of metabolic diseases.

SUMMARY OF THE INVENTION The present invention has been made in order to solve the above-mentioned problems in the prior art, and it is an object of the present invention to provide a modified taurine and a method for producing the modified taurine.

However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.

Hereinafter, various embodiments described herein will be described with reference to the drawings. In the following description, for purposes of complete understanding of the present invention, various specific details are set forth, such as specific forms, compositions and processes, and the like. However, certain embodiments may be practiced without one or more of these specific details, or with other known methods and forms. In other instances, well-known processes and techniques of manufacture are not described in any detail, in order not to unnecessarily obscure the present invention. Reference throughout this specification to "one embodiment" or "embodiment" means that a particular feature, form, composition, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Accordingly, the appearances of the phrase " in one embodiment "or" an embodiment "in various places throughout this specification are not necessarily indicative of the same embodiment of the present invention. In addition, a particular feature, form, composition, or characteristic may be combined in any suitable manner in one or more embodiments.

Unless defined otherwise in the specification, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

In one embodiment of the present invention, " taurine " is a kind of amino acid which is a food, which is hardly contained in plants but is widely distributed in animals and exhibits an inhibitory action on the sympathetic nerves of the brain, (LDL) cholesterol that induces atherosclerosis, angina pectoris, myocardial infarction, and the like, and is known to be effective for various diseases such as vascular diseases and dementia as well as platelet aggregation action in blood vessels. However, taurine is difficult to make a useful modification or composition having therapeutic ability for various diseases, and generally taurine is used as a raw material in an amino acid food state.

In one embodiment of the present invention, the term " modified taurine " refers to an atypical structure of irregular particles different from existing taurine, resulting in different physical properties. Also, due to the difference in physical properties, it has a remarkable therapeutic effect on metabolic diseases.

In the modified taurine of the present invention, the atomic distances of the existing taurine and the sulfur (S) connected with the carbon in the molecule (C) are different, and the values of the properties of Raman spectrum, FT-IR, TGA, melting point, . The modified taurine is used as an active ingredient of foods or pharmaceutical preparations or used for the synthesis of pharmaceutical preparations. It can be used in combination with a polar substance such as taurine, water (H ₂ O) and a methyl group (-CH ₃ ) "a is produced by mixing," taurine, water and molecular structures within a methyl group (-CH ₃₎ the composition "in" water and molecular structure within the polar group-containing material which has been removed a (-CH ₃₎ a polar substance with a " .

In one embodiment of the present invention, " polarity degree " means the degree of polarity of a solvent or a polar substance. Normally, water has values of 9, ethanol 5.2, methanol 5.1, acetone 5.1, propanol 4 and butanol 4. The difference in polarity between the polar materials mixed with such a solvent can affect the physical propensity of the particles dissolved in the solvent.

In one embodiment of the present invention, " obesity " refers to an excess of body fat, defined as a male obese when body fat is at least 25% of body weight and a female is at least 30% of body weight. Obesity occurs when the amount of calories consumed by the body exceeds the calories consumed by moving the body, and lifestyle such as overeating and lack of exercise are the causes of obesity. This is called simple obesity. On the other hand, endocrine system diseases, hypothalamic dysfunction, energy metabolism abnormalities can cause obesity, which is classified as symptomatic obesity. Obesity is also a cause of genetic factors. You can measure your obesity through your height and weight, and you can also diagnose it by measuring the thickness of your skin wrinkles using a caliper. Modified Broca's method and body mass index (BMI) are methods to calculate the obesity index that quantifies the degree of obesity. The ideal body weight method is a method of calculating the present body weight as a percentage by calculating the height [cm (cm) -100] X 0.9 as an ideal body weight. That is, in the ideal weight method, the obesity degree is equal to (in actual body weight - in the standard body) / 100% in the standard body. BMI is the weight divided by the height of the kidneys. If the current weight exceeds 20% of the ideal weight, and the BMI is above 30, it is called obesity.

Obese people appear to be fat-looking and can experience bruising and joint pain. In addition, diabetes, hypertension and other symptoms are accompanied.

In one embodiment of the present invention, " diabetes " is a disease caused by an abnormality in the relationship between glucose metabolism and blood glucose regulating hormone in vivo. Diabetes mellitus is classified as insulin dependent diabetes mellitus (Type 1 diabetes), non-insulin dependent diabetes mellitus (type 2 diabetes), and nutritional composition diabetes mellitus (MRDM). Type 2 diabetes, which accounts for more than 90% It is reported that the metabolic disease is caused by decreased insulin secretion of pancreatic beta cells due to genetic, metabolic and environmental factors or increased insulin resistance in peripheral tissues. In this regard, it is known that when body fat increases according to obesity, the insulin sensitivity is decreased. Especially, accumulation of abdominal fat is known to be related to glucose intolerance. In patients with type 2 diabetes, obesity and insulin resistance are closely related, and it is known that the greater the degree of obesity, the greater the insulin resistance. Accordingly, there is an example of developing an insulin sensitivity improving agent that can reduce insulin resistance, for example, a thiazolidinedione-based drug and biguanide as an obesity treatment agent. Some of the well-known obesity remedies to date include XenicalTM (Roche Pharmaceuticals, Switzerland), Reductil (TM), Abbott, USA) and Exolise (Atopama, France). However, since these drugs have an anti-obesity effect due to the inhibition of appetite suppression and lipid absorption inhibition rather than promote burning and decomposition of fat, they can not solve the problem of insulin resistance fundamentally and can not completely treat diabetes with obesity In addition, side effects such as heart disease, respiratory disease, and neurological diseases have been reported.

In one embodiment of the present invention, the term " metabolic syndrome " refers to a disorder in which various diseases such as diabetes, hypertension, hyperlipidemia, obesity, coronary or arteriosclerosis are caused by chronic metabolic disorders, Reaven GM, Diabetes, 1988, 37: 1595-1607). Metabolic syndrome is characterized by insulin resistance, hypertension, and dyslipidemia, most of which are accompanied by overweight or obesity. Metabolic syndrome is also a risk factor for cardiovascular disease and has been reported to be associated with death from all causes. Unlike type 1 diabetes, the prevalence of metabolic syndrome is higher in type 2 diabetic patients and it is known that type 2 diabetes mellitus is associated with metabolic syndrome (Bonora E, et al. Diabet Med , 2004, 21: 52-8; Ford ES, Diabetes Care., 2005, 28: 1769-78; Alexander CM, et al. Diabetes, 2003, 52: 1210-1214). In addition, studies on the association of macrovascular and microvascular complications of type 2 diabetes with the components of metabolic syndrome such as hypertension and dyslipidemia have been published (Mykkanen L, et al. Diabetologia, 1993, 36 : 553-559; Haffner SM, et al. Diabetes, 1992, 41: 715-722). The most serious problems of metabolic syndrome are the occurrence of chronic complications such as diabetic retinopathy, nephropathy, hyperlipidemia, cardiovascular disease (stroke, angina, myocardial infarction, peripheral vascular disease) (Wolf SP, Br Med Bull., 1993, 49: 642-652). Most of these chronic complications are irreversible after they have been developed. Until now, there is no way to completely block this process. If the proper treatment is not performed, serious symptoms will be caused and the patient will die. Therefore, for the effective management or treatment of metabolic syndrome with complex symptoms, it is ideal to have a blood glucose lowering effect for maintenance of normal blood sugar and at the same time to treat nephropathy, hepatopathy and hyperlipemia. However, And they are separately taking their hypoglycemic agents, hypotensive agents, and cholesterol drugs separately.

Korean Patent Laid-Open Publication No. 2008-0059575 discloses a method for treating a salt and metabolic disease of an regulator of PPAR, but there is a fear of side effects because it is chemically synthesized. In order to minimize such side effects, Korean Patent Laid-Open No. 2009-0114093 discloses an obesity and metabolic syndrome containing an extract of Evodiae Fructus, Imperatae Rhizoma and Citrus Unshiu Markovich as active ingredients Metabolic Syndrome or Syndrome X) and Korean Patent Publication No. 2010-0956278 discloses a composition for preventing or treating diabetes mellitus, A composition for treating or preventing diabetes or diabetic complications comprising an herbal extract as an active ingredient is disclosed.

In one embodiment of the present invention, " blood coagulation " refers to a phenomenon in which blood stiffenes when blood is leaked out of a blood vessel. As a constituent of human body, blood has various important functions such as oxygen and nutrients, the function and buffering function of waste products, maintenance of body temperature, control of osmotic pressure and maintenance of ion balance, maintenance of moisture, regulation of fluidity, maintenance and regulation of blood pressure, have.

Normal blood circulation facilitates blood circulation by complementary regulation of the blood coagulation system and thrombolysis system in the body. Among them, the mechanism of the blood coagulation system is that the platelets adhere to the blood vessel walls and coagulate to form platelet thrombus , It is reported that the blood coagulation system is activated and fibrin thrombus is formed centering on the platelet aggregation mass. The production of fibrin clot involves multiple steps of multiple clotting factors, activating thrombin involved in fibrin clotting, resulting in fibrin monomers from fibrinogen, fibrin monomers polymerized by calcium, and bound to platelets and endothelial cells And forms a cross-linked fibrin polymer by factor XIII, producing a permanent thrombus. Therefore, the activity inhibitor of thrombin can be used as a prophylactic and therapeutic agent very useful for various thrombotic diseases caused by excessive blood coagulation. In the endogenous thrombosis pathway, prothrombin activation after sequential activation of Factor XII, Factor XI, Factor IX and Factor X is ultimately known to activate thrombin, and thus a specific inhibition of blood coagulation factors is also important. . Until now, various anticoagulants such as heparin, coumarin, aspirin, and europine have been used for the prevention and treatment of thrombotic diseases. However, they are very expensive and have hemorrhagic side effects, gastrointestinal disorders and hypersensitivity And the use thereof is limited.

&Quot; Pharmaceutical composition " in one embodiment of the present invention means a composition to be administered for a specific purpose. For the purpose of the present invention, the pharmaceutical composition of the present invention includes modified taurine and is administered for prevention or treatment of metabolic diseases, and includes a sugar, a protein, and a pharmaceutically acceptable carrier, excipient or diluent . The above "pharmaceutically acceptable" carriers or excipients are those approved by the regulatory agency of the government or listed in government or other generally approved pharmacopoeias for use in vertebrates, and more particularly in humans . Pharmaceutical compositions comprising modified taurine suitable for parenteral administration may be in the form of a suspension, solution or emulsion in an oily or aqueous carrier and may contain formulatory agents such as suspending, stabilizing, solubilizing and / or dispersing agents can do. This form can be sterilized and liquid. It can be stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria or fungi. Alternatively, the pharmaceutical composition comprising the modified taurine may be in the form of a sterile powder for reconstitution with a suitable carrier before use. The pharmaceutical compositions may be presented in unit-dose form, in ampoules, or in other unit-dose containers, or in multi-dose containers. Alternatively, the pharmaceutical composition may be stored in a freeze-dried (lyophilized) condition requiring only the addition of sterile liquid carriers, e. G., Water for injections just prior to use. Immediately, the injection solutions and suspensions may be prepared from sterile powders, granules or tablets. Suitable excipients for pharmaceutical compositions comprising modified taurine include preservatives, suspending agents, stabilizers, dyes, buffers, antibacterial agents, antifungal agents, and isotonic agents, for example, sugars or sodium chloride. As used herein, the term "stabilizer" refers to a compound that is optionally used in the pharmaceutical compositions of the present invention to avoid the need for sulfite salts and to increase shelf life. Non-limiting examples of stabilizers include antioxidants.

The pharmaceutical composition may comprise one or more pharmaceutically acceptable carriers. The carrier may be a solvent or a dispersion medium. Non-limiting examples of pharmaceutically acceptable carriers include water, saline, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycols), oils, and suitable mixtures thereof.

Parenteral formulations can be sterilized. Non-limiting examples of sterilization techniques include filtration through a bacteria-inhibiting filter, terminal sterilization, incorporation of sterile agents, irradiation, heating, vacuum drying and freeze-drying.

In addition, the pharmaceutical composition according to the present invention is a composition comprising a polar substance having a methyl group (-CH ₃ ) in taurine, water and a molecular structure, which produces the modified taurine or modified taurine, , And the saccharide is characterized in that it is selected from the group consisting of monosaccharides, disaccharides and polysaccharides. In the above case, the saccharide is preferably included in 0.1 to 2 parts by weight of the modified taurine, and the amino acid is preferably included in the range of 0.1 to 0.5 parts by weight based on the modified taurine, but is not limited thereto.

In one embodiment of the present invention, the term " food composition " is used variously as a food composition for the improvement of metabolic diseases. The food composition containing the composition of the present invention as an active ingredient may be used in various foods, Gums, tea, vitamin complexes, powders, granules, tablets, capsules, confections, rice cakes and breads. Since the food composition of the present invention is modified and prepared from an existing food-grade food having little toxicity and side effects, it can be safely used for prolonged use for preventive purpose. When the composition of the present invention is contained in the food composition, the amount thereof may be added in a proportion of 0.1 to 100% of the total weight. Here, when the food composition is prepared in a beverage form, there are no particular limitations other than those containing the food composition at the indicated ratios and may contain various flavors or natural carbohydrates such as ordinary beverages as an additional ingredient. That is, natural carbohydrates include monosaccharides such as glucose, disaccharides such as fructose, sucrose and the like, and sugar sugars such as polysaccharide, dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol can do. Examples of the flavors include natural flavors (such as tau martin, stevia extract (for example, rebaudioside A and glycyrrhizin), and synthetic flavors (for example, saccharin and aspartame). The food composition of the present invention can be used as a food composition containing various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants, pectic acid and its salts, alginic acid and its salts, Stabilizers, antiseptics, glycerin, alcohols, carbonating agents used in carbonated beverages, etc. These components may be used independently or in combination. The ratio of these additives is not so important, Is generally selected in the range of 0.1 to 100 parts by weight per part.

In one embodiment of the invention, administration means introducing the composition of the present invention to a patient by any appropriate method, and the route of administration of the composition of the present invention may be administered through any conventional route so long as it can reach the target tissue have. Intraperitoneal, intraperitoneal, intradermal, intraperitoneal, intramuscular, subcutaneous, intradermal, intranasal, intrapulmonary, intrathecal, intrathecal, intraperitoneal, and intradermal administration may be carried out, In the case of a pharmaceutical composition for the prevention or treatment of metabolic diseases including taurine, it is preferably, but not exclusively, administered via oral administration or intravenous injection.

The metabolic disease treatment method of the present invention may include administering the pharmaceutical composition in a pharmaceutically effective amount. In the present invention, the effective amount may be determined depending on the kind of the disease, the severity of the disease, the kind and amount of the active ingredient and other ingredients contained in the composition, the type of the formulation and the age, body weight, general health condition, sex and diet, And the fraction of the composition, the duration of the treatment, the drug being co-administered, and the like.

In one embodiment of the present invention, the modified taurine produced by dissolving taurine in a first polar solvent while warming and adding a second polar material is used to adjust the difference in polarity between the first solvent and the second polar material to 5 or less , An absorption band intensity ratio of 891/847 at the positions 847, 891, 1182, 1256, 1427, and 1458 cm ^-1 on the Raman spectrum, a 1182/1256 absorption band intensity ratio, and a 1427/1458 absorption band intensity ratio of less than 1 do. In this embodiment, the onset point of the modified taurine provides modified taurine having a temperature of 330 ° C to 340 ° C and the water solubility of the modified taurine is 75 to 79g / L. The modified taurine has infrared spectroscopy and (FT-IR) 1650 provides to position ^-1 2800㎝ absorption wavelength is different from the taurine-modified taurine in the first and the polar solvent is water, a second polar substance is methanol, ethanol, propanol, butanol, acetone, ethyl , Ethyl acetate, and chloroform.

In one embodiment of the present invention, heating or heating can be performed by any method that can directly heat water or heat water such as a microwave oven. Removal of a polar substance having a methyl group (-CH ₃ ) in the molecular structure, which is a general polar solvent but not a solvent for taurine dissolution, can be used. Any method such as a heating method or a separation method can be used. In the case of alcohol, it must be removed by boiling above the boiling point of alcohol (about 78.4 ℃ for ethanol, about 64.7 ℃ for methanol). In the case of ethanol, the mixture is heated for 1 minute to 15 minutes based on 100 ml of the mixture at about 100 ° C under 1 atm.

In one embodiment of the present invention, when taurine (NH ₂ CH ₂ CH ₂ SO ₃ H) is dissolved in purified water and then a "polar substance having a methyl group (-CH ₃ ) in the molecular structure" is added, Is a polar material with taurine, water and a methyl group (-CH ₃ ) in the molecular structure, which is necessary to produce " modified taurine " which can be used as an active ingredient in pharmaceutical preparations, ≪ / RTI > can be prepared by "

In one embodiment of the present invention, in order to increase the solubility of taurine, water is heated to prepare an aqueous solution of taurine at a boiling point, and an alcohol or acetone, which is a polar substance having a methyl group (-CH ₃ ) in the molecular structure, taurine "of the resulting white semi-solid is formed which" taurine, water and molecular structure within the group composition containing a polar material with a (-CH ₃₎ "was prepared (see Fig. 1). The white semi-solid is aggregated with taurine, water and alcohol (or acetone), and when the temperature is lowered, taurine does not precipitate. When water and alcohol (or acetone) are removed, "modified taurine" do. That is, water and a polar substance having a methyl group (-CH ₃ ) in the molecular structure in a composition containing a polar material having a methyl group (-CH ₃ ) in the structure of taurine, water, , A "modified taurine" having different properties from the existing taurine is produced.

In one embodiment of the invention, "a methyl group (-CH ₃₎ a polar material or a polar solvent comprising or" is "a methyl group (-CH ₃₎ is an alkyl group comprising (C _n H _{2n +1)",} such as alcohols Polar material, and, when mixed with the aqueous taurine solution, should have the appropriate polarity to form the white semi-solid that produces " modified taurine ". The white semi-solid is a material formed from taurine, water and a polar material with a methyl group (-CH ₃ ) in the molecular structure. Examples of the polar material having a methyl group (-CH ₃ ) in the molecular structure that can be used include methanol, ethanol, propanol, butanol, acetone and the like. However, as the number of carbon atoms in the alcohol increases, the polarity is drastically reduced, This should be taken into account as the amount of solids formed is small. A composition containing a polar material having taurine, water and a methyl group (-CH ₃ ) in the molecular structure to produce the above "modified taurine" is generally prepared by adding 0.1 to 17.1 g of taurine per 30 ml of purified water under 1 atm , Heating at 100 ° C to dissolve, adding 1 to 1,000 ml of a "polar material having a methyl group (-CH ₃ ) in the molecular structure", and mixing. If the added amount of the taurine is less than the above range, the function as an intermediate for synthesis of the pharmaceutical preparation, that is, the therapeutic effect of the desired final pharmaceutical composition may be deteriorated. If the added amount is larger than the above range, there is a problem that the dissolution of taurine is not properly performed . If the amount of the "polar substance having a methyl group (-CH ₃ ) in the molecular structure" is less than the above range, there is a fear that "modified taurine" is not formed properly. The added amount of the "polar substance having a methyl group (-CH ₃ ) in the molecular structure" is not limited so far as "modified taurine" can be sufficiently produced, but 10 to 3,000 parts by weight is added to 100 parts by weight of the aqueous taurine solution .

In one embodiment of the present invention, the distance between atoms of carbon (C) and sulfur (S) is 1.7730 to 1.7779 (Å) and the average distance between atoms of sulfur (S) and three oxygen (O) is 1.452 to 1.462 (A), and wherein the maximum distance between atoms of sulfur (S) and three oxygen atoms (O) is 1.458 to 1.468 (A), wherein said modified taurine has positions 847, 891, 1182, 1256 , 1427, and 1458 cm ^-1 , wherein the ratio of 891/847 absorption band intensity, 1182/1256 absorption band intensity ratio, and 1427/1458 absorption band intensity ratio are all less than 1, wherein the modified taurine starts to melt Wherein the modified taurine has an onset point of 330 to 340 DEG C, and the modified taurine has a water solubility of 75 to 79 g / L, modified, characterized in that the maximum density of 1.74 to 1.76g / cm ³ taurine And providing the modified taurine provides a taurine-modified, characterized in that the absorption wavelength of 1650 to 2800 cm ^-1 in the infrared spectral position (FT-IR) is different from taurine.

In another embodiment of the present invention, there is provided a method for preparing a pharmaceutical composition comprising: (a) dissolving taurine in water; (b) adding alcohol to the above (a) to bind taurine, water, and alcohol; And (c) recrystallizing taurine by removing water and an alcohol from the step (b), wherein the water in step (a) is a solution of water corresponding to a saturated aqueous taurine solution The amount of the modified taurine used is 1 to 20 times the amount of the modified taurine.

Hereinafter, the present invention will be described in detail.

In the modified taurine of the present invention, the atomic distances of the existing taurine and the sulfur (S) connected with the carbon in the molecule (C) are different, and the values of the properties of Raman spectrum, FT-IR, TGA, melting point, . The modified taurine is used as an active ingredient of foods or pharmaceutical preparations or used for the synthesis of pharmaceutical preparations. It can be used in combination with a polar substance such as taurine, water (H ₂ O) and a methyl group (-CH ₃ ) "a is produced by mixing," taurine, water and molecular structures within a methyl group (-CH ₃₎ the composition "in" water and molecular structure within the polar group-containing material which has been removed a (-CH ₃₎ a polar substance with a " . The modified taurine of the present invention is expected to be widely used in the medical field because of its excellent effect of preventing and treating metabolic diseases.

Figure 1 according to the embodiment of the present invention an example, taurine, and water "that taurine by mixing a" molecular structure within a methyl group (-CH ₃₎ is a polar material in "to produce a" modified taurine "of white semi-solid is formed, (A: ethanol (B): methanol, C: propanol, D: butanol, E: acetone) containing water and a polar substance having a methyl group (-CH ₃ ) in the molecular structure.
2 is a Raman spectrum of taurine and modified taurine, according to one embodiment of the present invention.
FIG. 3 is a result of infrared (FT-IR) spectroscopic analysis of taurine and modified taurine (A: taurine, B: modified taurine) according to an embodiment of the present invention.
4 is a SEM analysis result of taurine and denatured taurine according to an embodiment of the present invention.
5 is a TGA graph of taurine and denatured taurine (A: TGA graph, B: first order differential TGA graph), according to one embodiment of the present invention.
FIG. 6 is a result of measuring the melting point of taurine and modified taurine (A: melting point graph, B: analysis report photograph) according to an embodiment of the present invention.
7 shows the results of water solubility measurement of taurine and modified taurine, according to an embodiment of the present invention.
Figures 8 and 9 are graphs showing prothrombin time, activated partial thromboplastin time, and thrombin time of mice treated with the pharmaceutical composition of the present invention, according to one embodiment of the present invention. Time) measurement results.
10 to 15 are graphs showing weight gain of a mouse treated with the pharmaceutical composition of the present invention, according to an embodiment of the present invention.
16 to 19 are graphs showing the results of GTT measurement of a mouse treated with the pharmaceutical composition of the present invention, according to an embodiment of the present invention.
20 to 23 are photographs showing liver, white adipose tissue (WAT), brown adipose tissue (BAT) and kidney tissue of a mouse treated with the pharmaceutical composition of the present invention, according to an embodiment of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for illustrating the present invention and that the scope of the present invention is not construed as being limited by these embodiments.

Composition design of composition

Prior to the experiment, components and composition ratios of the examples and comparative examples to be used in each experiment were designed. This is shown in Table 1. Specific production methods in each configuration are described in Example 1, Example 2, Comparative Example 1, and Comparative Example 2.

Examples 1-2 TauAlc DT15 Example 2-1 TauAlc 8.6 * + Intermediate 2.5 DT16 TauAlc 8.6 + Xyl 3.5 DT20 Example 2-2-1 TauAlc 8.6 + Ara 1.04 TauAlc 8.6 + Ara 5.2 TauAlc 8.6 + 7.8 TauAlc 8.6 + Xyl 1.04 TauAlc 8.6 + Xyl 5.2 TauAlc 8.6 + Xyl 7.8 TauAlc 4.3 + Rib 2.6 TauAlc 4.3 + Rib 6.5 Example 2-2-2 TauAlc 8.6 + Ara 1.04 TauAlc 8.6 + Ara 5.2 TauAlc 8.6 + 7.8 TauAlc 8.6 + Xyl 1.04 TauAlc 8.6 + Xyl 5.2 TauAlc 8.6 + Xyl 7.8 Example 2-3 TauAlc 4.3 + Glu 3.1 TauAlc 4.3 + Glu 7.75 TauAlc 4.3 + Mann 3.1 TauAlc 4.3 + Mann 7.75 TauAlc 4.3 + Fruc 7.75 Example 2-4-1 TauAlc 8.6 + Cat 3 + Bet 4 DT7 Example 2-4-2 TauAlc 8.6 + EGCG 1.5 + Bet 4 DT10 Example 2-5 TauAlc 8.6 + EGCG 1.5 + Bet 4 + Xyl 3.5 DT4 Comparative Example 1 Tau ** DT19 Comparative Example 2-1 Dec 1.04 Dec 5.2 Dec 7.8 Xyl 1.04 Xyl 5.2 Xyl 7.8 Rib 5.2 Rib 10.4 Comparative Example 2-2 Glu 6.2 Glu 12.4 Mann 3.1 Mann 6.2 Mann 12.4 Fruc 6.2 Fruc 12.4 Comparative Example 2-3-1 Tau 8.6 + Ara 1.04 Tau 8.6 + Ara 5.2 Tau 8.6 + 7.8 Tau 8.6 + Xyl 1.04 Tau 8.6 + Xyl 5.2 Tau 8.6 + Xyl 7.8 Tau 4.3 + Rib 2.6 Tau 4.3 + Rib 6.5 Comparative Example 2-3-2 Tau 8.6 + Ara 2.5 DT18 Tau 8.6 + Xyl 3.5 DT21 Comparative Example 2-4 Tau 4.3 + Glu 3.1 Tau 4.3 + Glu 7.75 Tau 4.3 + Mann 3.1 Tau 4.3 + Mann 7.75 Tau 4.3 + Fruc 7.75 Comparative Example 2-5-1 Tau 8.6 + Cat 3 + Bet 4 DT11 Comparative Example 2-5-2 Tau 8.6 + EGCG 1.5 + Bet 4 DT14 Comparative Example 2-6 Tau 8.6 + EGCG 1.5 + Bet 4 + Xyl 3.5 DT6

* TauAlc 8.6 means 8.6g of modified taurine.

** Tau is a conventional taurine.

In the above, Tau: taurine, TauAlc: modified taurine, Ara: arabinose, Xyl: xylose, Rib: ribose, Glu: glucose, Mann: mannose, Fruc: fructose, Cat: catechin, Bet: EGCG: Epigallocatechin gallate.

Example  1: Manufacture of "Modified Taurine"

1-1: Preparation of composition containing modified taurine

Taurine (8.6 g) was added to 30 ml of purified water and dissolved by heating in a microwave oven for about 60 seconds. Immediately after adding 60 ml of alcohol (ethanol (alcohol, alcohol, methanol, propanol, or butanol) To give a white semi-solid mixture (FIG. 1).

1-2: Preparation of modified taurine crystals

(1) Taurine (1.72 g) was added to 6 ml of purified water, taurine (4.3 g) was added to 15 ml of purified water, and taurine (8.6 g) was added to 28 ml of purified water. The mixture was heated in a microwave oven for 20 to 60 seconds After dissolving, immediately add 12 ml of normal temperature ethanol (in case of (1)), 30 ml of ethanol in case of (2) and 60 ml of ethanol in case of (3) Lt; / RTI > was prepared.

40 ml of purified water and 32 ml of purified water (in the case of (3)) heated to about 100 캜 were added to the mixture thus prepared, and then heated until the alcohol was removed in the microwave oven for about 3 to 5 minutes, .

Solid crystalline taurine crystals were prepared as in (3) above and then dried with a hot air dryer. (Specific composition ratio of each composition is shown in Table 1)

Example  2: Preparation of pharmaceutical compositions for the prevention or treatment of metabolic diseases

2-1: Preparation of modified taurine + 5-carbon sugar composition 1

A constant volume (2.5 g, 3.5 g) of pentane (xylose, arabinose) was added to 32 ml of purified water and heated for 30 seconds in a microwave oven to dissolve completely. Taurine (8.6 g) was added to 28 ml freshly, and the mixture was heated in a microwave oven for 60 seconds to dissolve. Immediately after adding 60 ml of ethanol, the mixture was stirred with a rod to prepare a mixture in which a white semi-solid was formed. After adding the aqueous solution, the composition was heated in a microwave oven for about 5 minutes until the alcohol was completely removed. (Specific composition ratio of each composition is shown in Table 1)

2-2-1: Preparation of modified taurine + 5-sugar composition 2

A constant volume (1.04 g, 2.6 g, 5.2 g, 6.5 g or 7.8 g) of pentose (xylose, arabinose, ribose) was added to 40 ml of purified water and heated for 30 to 50 seconds in a microwave oven to completely dissolve . (1) Taurine (4.3 g) was added to 15 ml of purified water or (2) taurine (8.6 g) was added to 30 ml of purified water. The mixture was heated to dissolve in a microwave oven for 40 to 60 seconds. Immediately, 30 ml ) Or 60 ml (in case of (2)) was added to the mixture while stirring to prepare a mixture in which a white semi-solid matter was formed. Then, the above-prepared aqueous solution of pentane was added to the mixture, And heated in a microwave oven for about 3 to 5 minutes until it was removed. Purified water was added to the mixed solution to adjust the total amount to 100 ml. (Specific composition ratio of each composition is shown in Table 1)

2-2-2: Preparation of modified taurine + 5-carbon sugar composition 3

40 ml of purified water was heated in a microwave oven for about 30 seconds and boiled. Taurine (8.6 g) was added to 30 ml of purified water and dissolved by heating in a microwave oven for about 60 seconds. Immediately after adding 60 ml of ethanol, To the mixture, 40 ml of boiled purified water was added to the mixture, and the mixture was heated (100 ° C) for about 5 minutes until the alcohol was completely removed from the microwave oven to prepare a composition .

A constant volume (1.04 g, 5.2 g, or 7.8 g) of pentose (xylose, arabinose) was added to 40 ml of purified water and heated for about 30 seconds in a microwave oven to completely dissolve the solution. The composition was mixed, heated in a microwave oven for about 30 seconds so that the mixture was mixed well, and purified water was added to adjust the total amount to 100 ml. (Specific composition ratio of each composition is shown in Table 1)

2-3: Preparation of modified taurine + 6-carbon sugar composition

A constant volume (3.1 g or 7.75 g) of hexose (mannose, glucose and fructose) was added to 40 ml of purified water and heated for about 50 seconds in a microwave oven to dissolve completely. Taurine (4.3 g) was added to 15 ml of purified water and dissolved by heating in a microwave oven for about 40 seconds. Immediately after adding 30 ml of ethanol, the mixture was stirred with a rod to prepare a mixture in which a white semi-solid was formed. After adding an aqueous solution of carbonic acid, the mixture was heated in a microwave oven for about 3 minutes and 30 seconds until the alcohol was completely removed, and then purified water was added to adjust the total amount to 100 ml. (Specific composition ratio of each composition is shown in Table 1)

2-4-1: Preparation of modified taurine + polyphenol + amino acid composition 1

Taurine (8.6 g) was added to 30 ml of purified water, and the mixture was completely dissolved by heating in a microwave oven for 1 minute and 20 seconds. Immediately after adding 60 ml of ethanol, the mixture was stirred with a rod to prepare a mixture in which a white semi-solid was formed. Next, 40 ml of purified water was heated to about 100 ° C for 1 minute using a microwave oven, catechin (3 g) and betaine (4 g) were added to dissolve the solution, and then added to the mixture. Ethanol was removed by heating. (Specific composition ratio of each composition is shown in Table 1)

2-4-2: Preparation of modified taurine + polyphenol + amino acid composition 2

Taurine (8.6 g) was added to 30 ml of purified water, and the mixture was completely dissolved by heating in a microwave oven for 1 minute and 20 seconds. Immediately after adding 60 ml of ethanol, the mixture was stirred with a rod to prepare a mixture in which a white semi-solid was formed. Next, 40 ml of purified water was heated to about 100 캜 for 1 minute by using a microwave oven, and EGCG (1.5 g) and betaine (4 g) were added to dissolve the mixture. Then, the mixture was added to the mixture, And the ethanol was removed by heating. (Specific composition ratio of each composition is shown in Table 1)

2-5: Preparation of modified taurine + polyphenol + amino acid + pentose composition

Taurine (8.6 g) was added to 30 ml of purified water, and the mixture was completely dissolved by heating in a microwave oven for 1 minute and 20 seconds. Immediately after adding 60 ml of ethanol, the mixture was stirred with a rod to prepare a mixture in which a white semi-solid was formed. Next, 40 ml of purified water was heated to about 100 占 폚 for 1 minute by using a microwave oven and dissolved by adding EGCG (1.5 g), betaine (4 g) and xylose (3.5 g) Then, the ethanol was removed by heating in a microwave oven for 5 minutes. (Specific composition ratio of each composition is shown in Table 1)

Comparative Example  1: Preparation of taurine aqueous solution

1-1: Preparation of taurine aqueous solution 1

60 ml of purified water was heated in a microwave oven for about 1 minute and then dissolved by adding taurine (8.6 g), followed by heating in a microwave oven for 3 minutes.

1-2: Preparation of taurine aqueous solution 2

Taurine (1.72 g, 4.3 g, or 8.6 g) was added to 30 ml of freshly purified water, heated and dissolved (100 ° C) in a microwave oven for about 1 minute, and then boiled 40 ml of purified water was added, and the mixture was heated in a microwave oven for about 2 minutes until boiling, and purified water was added to adjust the total amount to 100 ml. (Specific composition ratio of each composition is shown in Table 1)

Comparative Example  2: Preparation of pharmaceutical compositions for the prevention or treatment of metabolic diseases

2- 1: 5 charge  Composition manufacturing

A constant volume (1.04 g, 5.2 g, 7.8 g or 10.4 g) of pentose (xylose, arabinose, ribose) was added to 40 ml of purified water and the mixture was completely dissolved by heating in a microwave oven for about 30 seconds. 30 ml of purified water boiled in the range for about 30 seconds was added. 5 The solution was heated in a microwave oven for about 3 ~ 4 minutes until the solution was boiled, and purified water was added to adjust the total amount to 100 ml. (Specific composition ratio of each composition is shown in Table 1)

2- 2: 6 carbon  Composition manufacturing

A constant volume (3.1 g, 6.2 g or 12.4 g) of hexose (mannose, glucose and fructose) was added to 40 ml of purified water, and the mixture was completely dissolved by heating in a microwave oven for about 50 seconds and then boiled in a microwave oven for about 30 seconds 30 ml of purified water was added. 6 The solution was heated in a microwave oven for about 2 ~ 3 minutes until boiling solution was boiled, and then purified water was added to adjust the total amount to 100 ml. (Specific composition ratio of each composition is shown in Table 1)

2-3-1: Preparation of taurine + 5-sugar composition 1

A constant volume (1.04 g, 2.6 g, 5.2 g, 6.5 g or 7.8 g) of pentose (xylose, arabinose, ribose) was added to 40 ml of purified water and heated for 30 to 50 seconds in a microwave oven to completely dissolve . (1) Taurine (4.3 g) was added to 15 ml of purified water, or (2) taurine (8.6 g) was added to 30 ml of purified water. The solution was heated in a microwave oven for 40 to 60 seconds to dissolve the solution. . The mixture was heated for about 2 to 4 minutes until boiling in a microwave oven, and then purified water was added to adjust the total amount to 100 ml. (Specific composition ratio of each composition is shown in Table 1)

2-3-2: Preparation of taurine + pentose composition 2

60 ml of purified water was heated to about 100 ° C for 1 minute in a microwave oven and arabinose (2.5 g) and xylose (3.5 g) were added to taurine (8.6 g) Min. (Specific composition ratio of each composition is shown in Table 1)

2-4: Preparation of taurine + hexose composition

A constant volume (3.1 g or 7.75 g) of hexose (mannose, glucose and fructose) was added to 40 ml of purified water and heated for about 50 seconds in a microwave oven to dissolve completely. Taurine (4.3 g) was added to 15 ml of purified water and dissolved by heating in a microwave oven for about 40 seconds. The mixture was heated for about 2 minutes until boiling in a microwave oven, and purified water was added to adjust the total amount to 100 ml. (Specific composition ratio of each composition is shown in Table 1)

2-5-1: Preparation of taurine + polyphenol + amino acid composition 1

Taurine (8.6 g) was added to 30 ml of purified water and heated to about 1 minute and 20 seconds in a microwave oven to completely dissolve the taurine aqueous solution. Next, 40 ml of purified water was heated to about 100 ° C for 1 minute using a microwave oven, added with catechin (3 g) and betaine (4 g) to dissolve it, and then added to the aqueous taurine solution. Respectively. (Specific composition ratio of each composition is shown in Table 1)

2-5-2: Preparation of taurine + polyphenol + amino acid composition 2

Taurine (8.6 g) was added to 30 ml of purified water and heated to about 1 minute and 20 seconds in a microwave oven to completely dissolve the taurine aqueous solution. Next, 40 ml of purified water was heated to about 100 캜 for 1 minute by using a microwave oven, added with EGCG (1.5 g) and betaine (4 g) to dissolve, and then added to the aqueous taurine solution. Min. (Specific composition ratio of each composition is shown in Table 1)

2-6 Preparation of taurine + polyphenol + amino acid + pentose composition

Taurine (8.6 g) was added to 30 ml of purified water and heated to about 1 minute and 20 seconds in a microwave oven to completely dissolve the taurine aqueous solution. Next, 40 ml of purified water was heated to about 100 占 폚 in a microwave oven for 1 minute, dissolved by adding EGCG (1.5 g), betaine (4 g) and xylose (3.5 g) And then heated in a microwave oven for about 4 minutes. (Specific composition ratio of each composition is shown in Table 1)

Example  3. Identification of properties of modified taurine

Experimental Example  1: X-ray single crystal XRD )analysis

Experimental Example  One- 1: at 100K  Single crystal measurement

Single crystal X-ray analysis was performed on a Bruker SMART APEX II X-ray Diffractometer with Mo tube, graphite-monochromator and CCD area-detector at 50KV, 40mA and 100K conditions , And structural analysis was performed with Bruker SHELXTL software. The above specific conditions of execution are shown in Table 2 below.

Identification code 201412241t_0m Empirical formula C2 H7 N O3 S Formula weight 125.15 Temperature 100 (1) K Wavelength 0.71073 A Crystal system Monoclinic Space group P2 (1) / c Unit cell dimensions a = 5.2607 (2) A α = 90 ° b = 11.6303 (4) A ? = 94.015 (2)? c = 7.7903 (3) Å γ = 90 ° Volume 475.47 (3) Å ³ Z 4 Density (calculated) 1.748 Mg / m ³ Absorption coefficient 0.569 mm ^-1 F (000) 264 Crystal size 0.30 x 0.06 x 0.04 mm ³ Theta range for data collection 3.15 to 28.36 [deg.]. Index ranges -6 <= h <= 6, 0 <= k <= 15, 0 <= l <= 10 Reflections collected 1164 Independent reflections 1164 [R (int) = 0.0000] Completeness to theta = 28.36 ° 98.2% Absorption correction Multi-scan Max. and min. transmission 0.9776 and 0.8478 Refinement method Full-matrix least-squares on F ² Data / restraints / parameters 1164/0/73 Goodness-of-fit on F ² 1.102 Final R indices [I > 2sigma (I)] R1 = 0.0324, wR2 = 0.0779 R indices (all data) R1 = 0.0387, wR2 = 0.0797 Largest diff. peak and hole 0.433 and -0.509 e.a. ^-3

From the single crystal X-ray analysis of the modified taurine, the X-atom coordinates (x 10 ⁴ ) and the equivalent isotropic displacement parameter (Å ² x 10 ³ ) for the modified taurine are listed in Table 3, (Å) and angle (°) are shown in Table 4, and anisotropic displacement parameters (Åx 10 ³ ) for modified taurine are shown in Table 5, and hydrogen coordinates (× 10 ⁴ ) and isotropic displacement parameters (Å ² × 10 ³ ) are shown in Table 6, twist angle (°) of modified taurine is shown in Table 7, and hydrogen bonds (Å and °) of modified taurine are shown in Table 8.

x y z U (eq) S (1) 2983 (1) 8499 (1) 1500 (1) 9 (1) O (1) 5677 (2) 8384 (1) 2094 (2) 14 (1) O (2) 2700 (2) 9122 (1) -137 (2) 12 (1) O (3) 1588 (2) 7424 (1) 1465 (2) 14 (1) N (1) 2330 (3) 11304 (1) 1673 (2) 11 (1) C (1) 1616 (4) 9399 (1) 3033 (2) 11 (1) C (2) 2909 (4) 10567 (1) 3210 (2) 12 (1) U (eq) is defined as one third of the trace of the orthogonalized U ^ij tensor.

S (1) -O (3) 1.4495 (12) S (1) -O (2) 1.4653 (12) S (1) -O (1) 1.4659 (13) S (1) -C (1) 1.7775 (18) N (1) -C (2) 1.487 (2) N (1) -H (1A) 0.85 (2) N (1) -H (1B) 0.84 (3) N (1) -H (1C) 0.84 (2) C (1) -C (2) 1.520 (2) C (1) -H (1D) 0.9900 C (1) -H (1E) 0.9900 C (2) -H (2B) 0.9900 C (2) -H (2C) 0.9900 O (3) -S (1) -O (2) 112.98 (8) O (3) -S (1) -O (1) 113.83 (7) O (2) -S (1) -O (1) 110.89 (8) O (3) -S (1) -C (1) 107.02 (8) O (2) -S (1) -C (1) 105.80 (8) O (1) -S (1) -C (1) 105.62 (8) C (2) -N (1) -H (1A) 106.3 (15) C (2) -N (1) -H (1B) 112.0 (16) H (1A) -N (1) -H (1B) 111 (2) C (2) -N (1) -H (1C) 112.4 (15) H (1A) -N (1) -H (1C) 108 (2) H (1B) -N (1) -H (1C) 108 (2) C (2) -C (1) -S (1) 112.80 (13) C (2) -C (1) -H (1D) 109.0 S (1) -C (1) -H (1D) 109.0 C (2) -C (1) -H (1E) 109.0 S (1) -C (1) -H (1E) 109.0 H (1D) -C (1) -H (1E) 107.8 N (1) -C (2) -C (1) 112.14 (14) N (1) -C (2) -H (2B) 109.2 C (1) -C (2) -H (2B) 109.2 N (1) -C (2) -H (2C) 109.2 C (1) -C (2) -H (2C) 109.2 H (2B) -C (2) -H (2C) 107.9 Symmetry transformations used to generate equivalent atoms:

U ¹¹ U ²² U ³³ U ²³ U ¹³ U ¹² S (1) 8 (1) 7 (1) 13 (1) 0 (1) 2 (1) 0 (1) O (1) 10 (1) 11 (1) 22 (1) 2 (1) 0 (1) 1 (1) O (2) 12 (1) 11 (1) 13 (1) 1 (1) 2 (1) 0 (1) O (3) 15 (1) 9 (1) 20 (1) -2 (1) 5 (1) -5 (1) N (1) 10 (1) 8 (1) 13 (1) -1 (1) 2 (1) -1 (1) C (1) 11 (1) 10 (1) 12 (1) 0 (1) 2 (1) -1 (1) C (2) 11 (1) 11 (1) 12 (1) 0 (1) -1 (1) 1 (1) The anisotropic displacement factor exponent takes the form: -2π ² [h ² a * ² U ¹¹ + ... + 2 hka * b * U ¹² ]

x y z U (eq) H (1A) 2930 (40) 11960 (20) 1930 (30) 16 H (1B) 760 (50) 11347 (18) 1410 (30) 16 H (1C) 3040 (40) 11067 (19) 800 (30) 16 H (1D) -213 9512 2686 13 H (1E) 1739 9010 4166 13 H (2B) 2336 10962 4241 14 H (2C) 4775 10455 3381 14

O (3) -S (1) -C (1) -C (2) 179.82 (12) O (2) -S (1) -C (1) -C (2) -59.46 (14) O (1) -S (1) -C (1) -C (2) 58.19 (14) S (1) -C (1) -C (2) -N (1) 71.01 (18) Symmetry transformations used to generate equivalent atoms:

D-H ... A d (D-H) d (H ... A) d (D ... A) <(DHA) N (1) -H (1A) ... O (1) # 1 0.85 (2) 1.94 (2) 2.7808 (19) 170 (2) N (1) -H (1A) ... S (1) # 1 0.85 (2) 2.99 (2) 3.7591 (16) 152.0 (19) N (1) -H (1B) ... O (2) # 2 0.84 (3) 2.08 (2) 2.870 (2) 156 (2) N (1) -H (1B) ... O (3) # 3 0.84 (3) 2.47 (2) 2.910 (2) 113.3 (18) N (1) -H (1B) ... S (1) # 2 0.84 (3) 2.90 (2) 3.6064 (17) 143 (2) N (1) -H (1C) ... O (2) # 4 0.84 (2) 2.34 (2) 2.992 (2) 134.0 (18) N (1) -H (1C) ... O (1) # 4 0.84 (2) 2.48 (2) 3.205 (2) 144.1 (19) N (1) -H (1C) ... S (1) # 4 0.84 (2) 2.89 (2) 3.6186 (18) 145.4 (18) 2, -y + 2, -z # 3 -x, y + 1/2, -z + -z + 1/2 # 4 -x + 1, -y + 2, -z

Experimental Example  One- 2: at 296K  Single crystal measurement

The single crystal X-ray analysis was carried out using an XRD instrument (BRUKER AXS) equipped with an Mo tube, an adjustable graphite monochromator, a SMART 3-Axis Goniometer, and a CCD area-detector (APEX II 4K CCD Detector) SMART APEX II) at 50KV, 40mA and 296K (room temperature), and structural analysis was performed with Bruker SHELXTL software. The above-mentioned specific operating conditions are shown in Table 9 below.

Identification code och08-1 Empirical formula C2 H7 N O3 S Formula weight 125.15 Temperature 296 (2) K Wavelength 0.71073 A Crystal system Monoclinic Space group P2 _{1 / c} Unit cell dimensions a = 5.2771 (2) A α = 90 °. b = 11.6376 (4) A ? = 94.113 (2)? c = 7.9190 (3) Å gamma = 90 [deg.]. Volume 485.08 (3) Å ³ Z 4 Density (calculated) 1.714 Mg / m &lt; ³ &gt; Absorption coefficient 0.558 mm ^-1 F (000) 264 Crystal size 0.30 x 0.20 x 0.10 mm ³ Theta range for data collection 3.117 to 26.406 [deg.]. Index ranges -6 < = h < = 6,
-14 < = k < = 14,
-9 <= l <= 9 Reflections collected 6712 Independent reflections 995 [R (int) = 0.0305] Completeness to theta = 25.242 ° 99.9% Refinement method Full-matrix least-squares on F ² Data / restraints / parameters 995/0/66 Goodness-of-fit on F ² 1.106 Final R indices [I > 2sigma (I)] R1 = 0.0271, wR2 = 0.0690 R indices (all data) R1 = 0.0279, wR2 = 0.0702 Extinction coefficient 0.74 (3) Largest diff. peak and hole 0.340 and -0.410 e.A- ³

From the single crystal X-ray analysis of the modified taurine, the X-atom coordinates (x 10 ⁴ ) and the equivalent isotropic displacement parameter (Å ² x 10 ³ ) for the modified taurine are shown in Table 10, (Å) and angle (°) are shown in Table 11, and anisotropic displacement parameters (Åx 10 ³ ) for modified taurine are shown in Table 12, and hydrogen coordinates (× 10 ⁴ ) and isotropic displacement parameters (Å ² × 10 ³ ) are shown in Table 13, twist angle (°) of modified taurine is shown in Table 14, and hydrogen bonds (Å and °) of modified taurine are shown in Table 15.

x Y z U (eq) S (1) 2967 (1) 8487 (1) 1492 (1) 22 (1) O (1) 2682 (2) 9108 (1) -114 (1) 29 (1) O (3) 5640 (2) 8371 (1) 2072 (2) 36 (1) O (2) 1581 (3) 7415 (1) 1460 (2) 36 (1) C (2) 2894 (3) 10548 (1) 3186 (2) 27 (1) C (1) 1606 (3) 9384 (1) 2997 (2) 25 (1) N (1) 2361 (3) 11292 (1) 1684 (2) 25 (1) U (eq) is defined as one third of the trace of the orthogonalized U ^ij tensor.

S (1) -O (2) 1.4452 (12) S (1) -O (3) 1.4582 (12) S (1) -O (1) 1.4609 (12) S (1) -C (1) 1.7750 (16) C (2) -N (1) 1.482 (2) C (2) -C (1) 1.518 (2) C (2) -H (2A) 0.9700 C (2) -H (2B) 0.9700 C (1) -H (1A) 0.9700 C (1) -H (1B) 0.9700 N (1) -H (1C) 0.8900 N (1) -H (1D) 0.8900 N (1) -H (1E) 0.8900 O (2) -S (1) -O (3) 113.75 (8) O (2) -S (1) -O (1) 113.06 (8) O (3) -S (1) -O (1) 110.89 (7) O (2) -S (1) -C (1) 106.89 (8) O (3) -S (1) -C (1) 105.75 (8) O (1) -S (1) -C (1) 105.80 (7) N (1) -C (2) -C (1) 112.59 (12) N (1) -C (2) -H (2A) 109.1 C (1) -C (2) -H (2A) 109.1 N (1) -C (2) -H (2B) 109.1 C (1) -C (2) -H (2B) 109.1 H (2A) -C (2) -H (2B) 107.8 C (2) -C (1) -S (1) 113.03 (11) C (2) -C (1) -H (1A) 109.0 S (1) -C (1) -H (1A) 109.0 C (2) -C (1) -H (1B) 109.0 S (1) -C (1) -H (1B) 109.0 H (1A) -C (1) -H (1B) 107.8 C (2) -N (1) -H (1C) 109.5 C (2) -N (1) -H (1D) 109.5 H (1C) -N (1) -H (1D) 109.5 C (2) -N (1) -H (1E) 109.5 H (1C) -N (1) -H (1E) 109.5 H (1D) -N (1) -H (1E) 109.5 Symmetry transformations used to generate equivalent atoms:

U ¹¹ U ²² U ³³ U ²³ U ¹³ U ¹² S (1) 20 (1) 17 (1) 29 (1) 1 (1) 3 (1) -1 (1) O (1) 32 (1) 29 (1) 26 (1) 2 (1) 5 (1) 0 (1) O (3) 22 (1) 28 (1) 55 (1) 4 (1) -2 (1) 6 (1) O (2) 41 (1) 24 (1) 45 (1) -4 (1) 11 (1) -13 (1) C (2) 30 (1) 25 (1) 26 (1) -4 (1) -3 (1) 2 (1) C (1) 26 (1) 26 (1) 25 (1) 2 (1) 5 (1) 1 (1) N (1) 24 (1) 21 (1) 29 (1) -2 (1) 4 (1) -2 (1) The anisotropic displacement factor exponent takes the form: -2π ² [h ² a * ² U ¹¹ + ... + 2 hka * b * U ¹² ]

x y z U (eq) H (2A) 2317 10932 4176 32 H (2B) 4715 10437 3369 32 H (1A) -179 9498 2657 30 H (1B) 1717 9000 4087 30 H (1C) 3162 11016 820 37 H (1D) 2904 12002 1921 37 H (1E) 696 11305 1410 37

N (1) -C (2) -C (1) -S (1) 70.52 (16) O (2) -S (1) -C (1) -C (2) 179.40 (11) O (3) -S (1) -C (1) -C (2) 57.86 (13) O (1) -S (1) -C (1) -C (2) -59.84 (13) Symmetry transformations used to generate equivalent atoms:

D-H ... A d (D-H) d (H ... A) d (D ... A) <(DHA) N (1) -H (1C) ... O (1) 0.89 2.35 2.9239 (18) 122.5  N (1) -H (1C) ... O (1) # 1 0.89 2.31 3.0121 (18) 136.2  N (1) -H (1C) ... O (3) # 1 0.89 2.52 3.250 (2) 139.5  N (1) -H (1D) ... O (3) # 2 0.89 1.92 2.7913 (18) 166.5  N (1) -H (1E) ... O (1) # 3 0.89 2.05 2.8931 (18) 157.9  N (1) -H (1E) ... O (2) # 4 0.89 2.50 2.9382 (19) 111.0 Symmetry transformations used to generate equivalent atoms: # 1 -x + 1, -y + 2, -z # 2 -x + 1, y + 1/2, -z + , -z # 4 -x, y + 1/2, -z + 1/2

Experimental Example  1-3: Single crystal comparison of taurine with modified taurine

From the results of the single crystal X-ray analysis of the modified taurine derived from the results of Tables 2 to 15, the atomic characteristics of the modified taurine are shown in Table 16 in comparison with the taurine. Comparative data of taurine are available from published papers (Y. Okaya, Acta Cryst. 1966. (21) 726-35; David E. Hibbs et al., Chem. 84, and JA Beukes et al., Phys. Chem., Phys., 2007, 9, 4709-20).

SC
Atomic distance (Å) CN
Atomic distance (Å) Density (Mg / m ³⁾ CH
(4H)
Average distance between atoms (Å) SO
(3O) Average distance between atoms
(Maximum distance) (A) NH
(3H)
Average distance between ionic molecules (Å) Temperature One Modified taurine 1.7775 1.487 1.748 0.99 1.4602
(1.4659) 0.843 100K 2 Modified taurine 1.7750 1.482 1.714 0.97 1.4548
(1.4609) 0.89 296K 3 Taurine 1.7858 1.4910 1.734 1.10 1.4659
(1.4720) 1.045 100k 4 Taurine 1.780 1.484 1.70 0.9525 1.458
(1.465) 0.847 293k 5 Taurine 1.7815 1.4862 1.738 1.10 1.4648
(1.4696) 1.045 120k 6 Taurine 1.7818 1.4809 1.709 1.10 1.4581
(1.4639) 1.045 296k

The atom distances in Table 16 are summarized in Table 17.

SC distance
(Difference due to temperature change) SO Average Distance
(Difference due to temperature change) SO maximum distance
(Difference due to temperature change) ① Taurine 1.780 to 1.7858Å
(0.0058) 1.458 to 1.4659Å
(0.0079) 1.4639 to 1.4720Å
(0.0081) ② Modified taurine 1.7750 to 1.7775Å
(0.0025) 1.4548 to 1.4602Å
(0.0054) 1.4609 to 1.4659Å
(0.005) Distance Difference Ratio with Temperature Variation
(② / ①) × 100% (0.0025 / 0.0058) x100
= 43.1% (56.9% reduction) (0.0054) / (0.0079) x100
= 68.4% (down 31.6%) (0.005) / (0.0081) x100
= 61.7% (down by 38.3%)

As a result of the experiment, the bond length changes of the atoms in the XRD results of the temperature changes of 100 K and 296 K (room temperature) were as follows.

① The bond length of S-C and S-O tended to be longer as the temperature decreased from 296K to 100K. This can be interpreted as a phenomenon caused by the decrease in the mobility of molecules as the temperature decreases and the hydrogen bonds having the direction of bonding become stronger with other molecules adjacent to each other.

② The change of SC distance, SO average distance and SO maximum length, which indicates the binding strength when the temperature was decreased from 296K to 100K, was 56.9%, 31.6% and 38.3% shorter than that of normal taurine, respectively. Also, at the same temperature, the maximum distance between the SO atoms of modified taurine was almost the same as the average distance between SO atoms of normal taurine, and the SC atom binding distance of modified taurine was 0.007 ~ 0.008Å shorter than that of normal taurine at the same temperature. Overall, it was found that the binding distance between SC atoms was less than 1.78 Å for modified taurine and 1.78 Å for normal taurine regardless of temperature. Thus, the difference in bond lengths means that the interatomic electron density distribution of the modified taurine molecule is different from that of normal taurine, which is affected by the -CH ₂ CH ₂ - group bound to the -SO ₃ ^- group in the taurine molecule .

③ In addition, the modified taurine showed less hydrogen bonding property than taurine. In Table 17, the maximum distance of the S-O bonds indicates the degree of hydrogen bonding with N-H of adjacent molecules, and the longer the length, the stronger the hydrogen bond. At the same temperature, the S-O maximum distance of normal taurine was 0.003 ~ 0.006 Å longer than that of modified taurine. This indicates that the distribution of the electron density in the molecule is more concentrated in the specific bond in the case of modified taurine and does not show a large change in the external influence (hydrogen bonding).

Experimental Example  2: Raman Spectrum analysis

In order to confirm the structural difference between taurine and &quot; modified taurine &quot;, Raman analysis was commissioned to Korea Polymer Research Institute and the results are shown in Fig.

All of the &quot; modified taurine &quot; crystals used for the analysis were solid state crystals prepared in the case of Example 1-2 (3).

The analytical equipment and conditions are as follows.

(1) Analytical instrument: Nanofinder FLEX G (Lambda Ray)

(2) Source: 532 nm

(3) Range: 200 to 3600 cm ^-1

(4) Exposure time, accumulation: 3 sec / 20 time

(5) Spatial resolution: about 0.5㎛

(6) Peak resolution: 1 cm ^-1

As shown in Fig. 2, the &quot; modified taurine &quot; confirmed that the absorption intensity of the red dot region was somewhat different from that of the conventional taurine. Journal of Raman Spectroscopy, Vol. As ^1, -CH ₂ of both taurine molecule ^{- - 27, 507-512 (1996)} Raman data and look at the result shown in the position 847, 891, 1182, 1256, 1427, compared 1458㎝ measured by reference set out in, - It was confirmed that the absorption band related to the vibration mode of C ₂ H ₄ -. Thus, the "modified taurine" affects the vibrations of -CH ₂ ^- and -C ₂ H ₄ ^{- in} the molecule during crystal formation and shows a difference in the intensity of the Raman absorption band. That is, the difference in the Raman absorption band shows that there is a difference in molecular properties between taurine and "modified taurine".

Experimental Example 3: FT - IR (Infrared spectroscopy, Fourier Transform Infrared Spectroscopy) analysis

Infrared (FT-IR) spectroscopy was performed by the Korea Polymer Research Institute to confirm structural differences between taurine and "modified taurine". The results are shown in FIG.

The analytical equipment and conditions are as follows.

(1) Analytical instrument: JASCO FT-IR 4100

(2) Measurement mode: ATR mode

(3) Range: 600 to 4000 cm ^-1

(4) Number of scans: 32

(5) Peak resolution: 4 cm ^-1

As shown in Fig. 3, the infrared spectroscopic absorption spectra of taurine and &quot; modified taurine &quot; show differences in the infrared spectral absorption wavelength of 1650-2800 cm ^{&lt; -1} &gt;

This is described in Journal of Raman Spectroscopy, Vol. The SO ₃ H of taurine is replaced by an external water molecule (H ₂ O), which is a water molecule of the taurine, as shown in Fig. 27, 507-512 (1996) and G. Socrates, "Infrared and Raman Characteristic Group Frequencies", John Wiley & Sons, ) And SO ₃ ^- H ₃ O ⁺ . In addition, the oscillation mode of NH ₃ shows infrared absorption at wavelengths of 1173, 1508, 1614, 3044 and 3211 cm ^-1 , the oscillation mode of SO ₃ shows infrared absorption at wavelengths of 1037, 1204 and 1303 cm ^-1 , Infrared absorption at wavelengths of 1527 and 3523 cm ^-1 due to bonding is not seen. Thus, both taurine and "denatured taurine" have the same structure as ionized (H ₃ N ⁺ CH ₂ CH ₂ SO ₃ ^- ), but show a slight difference in the binding strength to SO ₃ and adjacent NH ₃ in the crystal. Indicating that there is a difference in the intensity of intermolecular bonding in the crystals of ionized, taurine and &quot; modified taurine &quot;.

Experimental Example  4: Electron Microscope ( Scanning Electron Microscope , SEM ) analysis

SEM analysis was performed to observe the surface and shape of taurine and &quot; modified taurine &quot;, and the results are shown in Fig.

The analytical equipment and conditions are as follows.

(1) Analytical instrument: HITACHI (S-2700), JAPAN

(2) Electron gun: Tungsten filament type

(3) Resolution: 4.0 nm

(4) Accelerating Voltage: 15.0 kV

4, the taurine observed by an electron microscope (SEM) is of a flaky structure like a crystal column, and the enlarged surface is also smooth. The "modified taurine" has a smaller crystal grain size than the taurine, And it was confirmed that some crystals of taurine were also mixed with each other. From the enlarged photograph of "modified taurine," we could confirm that the surface of the taurine was attached with "modified taurine." Such a shape is formed by water and a polar material with a methyl group (-CH ₃ ) in the molecular structure during manufacture to form small spherical particles having a wide distribution. Because of such particle shape, "modified taurine" has a larger surface area than taurine of the same mass, so it is presumed that hydration by adsorption of moisture in air is easier. At this time, the average particle size of taurine was 222.06 mu m and the median particle size was 192.92 mu m, while the mean particle size of the modified taurine was 190.84 mu m and the median particle size was 122.47 mu m. Thus, it can be seen that the particle sizes of taurine and modified taurine are significantly different.

Experimental Example  5: Thermal weight ( TGA , Thermogravimeteric 분석 ) analysis

Thermal diffraction analysis was performed to confirm the difference between "taurine" and "modified taurine", and the results are shown in FIG.

The analytical equipment and conditions are as follows.

(1) Analytical instrument: TGA 7 (Perkin-Elmer)

(2) Atmosphere: N ₂ gas

(3) Heating rate: 20 ° C / min

(4) Range: 50 to 600 ° C

As shown in FIG. 5, TGA represents the weight reduction of the sample with increasing temperature. In the case of "modified taurine" there is a slight reduction in weight from 150 ° C, which is due to the desorption of water molecules from the hydrated SO ₃ of the crystal surface or by thermal degradation at the surface of very small "modified taurine" It seems to be a phenomenon that appears to progress a little faster. Small particles of "modified taurine" increase the exposed area to heat, so thermal reactivity appears faster than taurine. As shown in the first derivative of TGA, the first decomposition temperature of the modified taurine is 359 ° C, the final decomposition temperature is 396 ° C, and the taurine decomposes at 362 ° C and 394 ° C. This is because the initial tearing occurs first because the modified taurine has a small particle size, but the final decomposition temperature shows higher characteristics.

Experimental Example  6: Melting point ( melting point ) analysis

A melting point analysis was conducted to confirm the difference between the taurine and the &quot; modified taurine &quot;, and the results are shown in Fig.

The analytical equipment and conditions are as follows.

(1) Analytical instrument: MPA100 (SRS; Stanford Research System)

(2) Starting temperature: 200 DEG C

(3) Heating rate: 10 ° C / min

As shown in FIG. 6, it was found that the melting point (onset point basis) of "modified taurine" was about 10 ° C. higher than the melting point of taurine (335.7 ° C., 336.6 ° C. ; And 337 ° C), indicating that the bond strength between the ionized molecules (H ₃ N ⁺ CH ₂ CH ₂ SO ₃ ^- ) in the crystals, such as the absorption intensity or absorption wavelength of the Raman or FT- This is a phenomenon that appears to be different.

Experimental Example  7: Water solubility analysis

In order to confirm the difference between taurine and "modified taurine", the water analysis (OECD Test Guideline 105) was submitted to the Korean Polymer Research Institute and the results are shown in FIG.

As shown in Fig. 7, the water solubility of taurine was 74 g / L, but the water solubility of "modified taurine" was 77 g / L.

As we have seen, the convergence of the distribution of electrons within a specific bond, as evidenced by the monocrystalline measurement of metamorphic taurine, affects the polarization of the electron density around a particular bond, and this shows a difference in the Raman spectrum. General taurine of -NH ₃ ⁺ of the absorption peak of 1172.05 cm ^-1, 3043.6 cm ^-1 absorption band in the IR spectrum and -SO ₃ ^- in the absorption band of 1204.45 cm ^-1 absorption band of the taurine-modified -NH ₃ ⁺ is 1173.77 cm ^{- _{1, 3044.57 cm -1, -SO 3}} - the 1205.5 cm ^{- 1} in the 1 ~ 2cm ^-1 blue shift is, this indicates that the bond length becomes shorter stronger bond strength jyeotdaneun, the degeneration process in the electron density modified taurine molecule .

That is, the modified taurine has a stronger electron fragmentation in the bond of -SO ₃ ^- than the normal taurine, and the ionic characteristic of -NH ₃ ⁺ is stronger, and the ionic bonding force is stronger than the hydrogen bond as the adjacent molecule and amphoteric molecule. It was found that the melting point was high and the solubility in water was also high. Therefore, it was found that the modified taurine has a stronger ion - binding property than the normal taurine by changing the electron density distribution in the taurine molecule through the denaturation process.

Example 4. Confirmation of the therapeutic effect of metabolic diseases

Anticoagulant activity evaluation

The activity of anti-thrombosis (anti-blood coagulation) was assessed in accordance with the previously reported method. Sysmex CA-1500 (Siemens Healthcare, Germany), an automatic blood coagulation test device, was used for PT, aPTT and TT analysis. Thromborel S, actin and thrombin were respectively installed and the PT was used for prothrombin time, aPTT (Activated partial thromboplastin time) and TT (thrombin time), respectively. Sufficient sample volumes for these three assays were approximately 400 uL as a mixture of 80: 20 ratios of plasma and test material.

A total of 23 to 25 mL of blood was collected from a healthy Korean adult male using a vacutainer (3.2% sodium citrate) exclusively for blood coagulation test and immediately centrifuged at 4 ° C and 2500 rpm for 10 minutes to separate the plasma, Were used for the experiment.

In this experiment, blood coagulation time (sec) of PT, aPTT and TT was compared statistically (%) compared with the third control distilled water (purified water) Respectively. Statistical analysis was performed by using SPSS IBM version 21.0. In vitro activity of anti-coagulation in vitro between the test substances was analyzed by Oneway ANOVA at p <0.05 level. The significance comparison between groups was analyzed by Duncan's test.

As a control, 37.5 mg of aspirin was completely dissolved in 1 ml of ethanol, 4 ml of purified water was added, and the mixture was aspirin at a concentration of 7.5 mg / ml.

Prothrombin time, activated partial thromboplastin time and thrombin time were measured by mixing 20 μl of the samples prepared in Examples 1 and 2 with 80 μl of plasma, 9, and Tables 18 to 20. As a control, aspirin was used. Third distilled water (purified water) was used as a solvent control instead of the sample.

Test substance (g / dL) N PT aPTT TT Average Standard Deviation Average Standard Deviation Average Standard Deviation Control Purified water 3 0.00 0.00 0.00 0.00 0.00 0.00 Control Asp 7.5 mg / ml 3 9.90 0.24 7.31 0.79 13.59 1.79 Comparative Example 2-1 Dec 1.04 3 0.56 0.98 2.51 0.92 2.09 0.53 Dec 5.2 3 5.93 1.47 3.72 1.76 13.40 1.01 Dec 7.8 3 9.60 1.29 6.39 1.90 22.92 1.22 Xyl 1.04 3 0.85 0.85 1.23 1.35 2.68 0.02 Xyl 5.2 3 4.52 1.29 5.70 0.91 14.59 1.49 Xyl 7.8 3 7.63 1.47 6.47 2.12 24.41 1.22 Comparative Example
1-2 Tau 1.72 3 0.00 0.85 -2.41 0.81 3.58 0.92 Tau 4.3 3 0.56 0.98 -4.35 1.17 9.83 1.63 Tau 8.6 3 4.80 1.29 -4.01 0.33 21.13 0.55 Comparative Example
2-3-1 Tau 8.6 + Ara 1.04 3 4.80 0.49 -4.01 0.41 22.03 0.69 Tau 8.6 + Ara 5.2 3 9.04 1.29 -1.06 0.67 33.64 2.10 Tau 8.6 + 7.8 3 12.71 1.47 0.83 1.35 42.57 1.38 Tau 8.6 + Xyl 1.04 3 4.80 0.98 -3.73 0.85 24.11 0.22 Tau 8.6 + Xyl 5.2 3 8.76 0.49 0.47 1.97 36.32 1.33 Tau 8.6 + Xyl 7.8 3 12.99 1.29 1.73 1.95 45.54 0.77 Examples 1-2 TauAlc 1.72 3 2.27 1.78 -1.19 1.26 4.06 0.46 TauAlc 4.3 3 2.26 1.76 -2.57 0.42 9.39 1.11 TauAlc 8.6 3 4.82 1.32 -2.73 1.69 20.64 1.25 Example
2-2-1 TauAlc 8.6 + Ara 1.04 3 7.66 2.99 0.18 1.56 21.25 0.59 TauAlc 8.6 + Ara 5.2 3 12.46 0.43 2.40 0.54 32.21 1.68 TauAlc 8.6 + 7.8 3 16.71 0.54 4.03 1.08 40.35 3.18 TauAlc 8.6 + Xyl 1.04 3 6.80 0.03 -0.67 1.93 25.64 1.75 TauAlc 8.6 + Xyl 5.2 3 11.05 0.05 1.11 0.30 35.33 1.43 TauAlc 8.6 + Xyl 7.8 3 14.73 0.56 4.89 0.50 43.77 2.47 Example
2-2-2 TauAlc 8.6 + Ara 1.04 3 4.25 0.87 -1.52 3.58 21.58 1.26 TauAlc 8.6 + Ara 5.2 3 11.62 0.52 1.04 1.70 37.19 0.52 TauAlc 8.6 + 7.8 3 13.60 0.07 1.46 1.06 41.92 3.15 TauAlc 8.6 + Xyl 1.04 3 5.95 0.88 -0.85 0.64 27.86 3.52 TauAlc 8.6 + Xyl 5.2 3 10.20 0.85 1.46 1.00 36.27 1.23 TauAlc 8.6 + Xyl 7.8 3 13.88 0.56 3.18 1.80 45.01 1.88

As shown in Table 18, the PT delay rate was increased when treated with the modified taurine (TauAlc) alone or with the sugar as compared with the taurine (Tau), and when the modified taurine (TauAlc) and the sugar were treated together, (Asp) of 7.5 mg / dL or more in the case of the composite form having a composition of 5.2 to 7.8 g of Xyl or arabinose (Ara) .

Test substance (g / dL) N PT aPTT * TT Average Standard Deviation Average Standard Deviation Average Standard Deviation Control Purified water 3 0.00 0.00 0.00 0.00 0.00 0.00 Control Asp 7.5 mg / ml 3 17.51 2.72 16.28 2.04 20.96 5.10 Comparative Example 2-1 Rib 5.2 3 8.47 2.24 9.17 1.42 23.15 8.20 Rib 10.4 3 14.97 2.59 12.46 3.16 52.50 7.63 Comparative Example 2-2 Gluc 6.2 3 1.69 0.85 2.22 0.73 16.24 3.09 Gluc 12.4 3 2.26 1.29 2.89 0.78 27.82 7.79 Comparative Example 1-2 Tau 4.3 3 1.69 0.85 -0.29 1.17 11.18 5.29 Comparative Example
2-3-1 Tau 4.3 + Rib 2.6 3 4.80 0.49 1.65 1.03 20.57 6.88 Tau 4.3 + Rib 6.5 3 10.73 0.49 4.25 0.98 34.61 6.87 Comparative Example 2-4 Tau 4.3 + Gluc 3.1 3 0.00 0.85 -1.25 1.61 19.23 3.82 Tau 4.3 + Gluc 7.75 3 1.98 1.29 -1.54 1.09 30.30 4.29 Examples 1-2 TauAlc 4.3 3 0.85 0.85 -2.03 2.03 12.49 7.15 Example
2-2-1 TauAlc 4.3+ Rib 2.6 3 5.37 0.49 2.61 2.79 21.84 6.34 TauAlc 4.3+ Rib 6.5 3 11.02 0.85 3.96 0.78 35.88 6.33 Example
2-3 TauAlc 4.3+ Gluc 3.1 3 0.85 0.85 -1.06 1.18 24.16 4.40 TauAlc 4.3+ Gluc 7.75 3 3.11 2.13 -0.56 2.30 41.80 15.69

* Excluding one sample showing extreme value

As shown in Table 19, when the modified taurine (TauAlc) was treated alone or in combination with the sugar, the TT delay rate was increased compared with the taurine (Tau). When the modified taurine (TauAlc) and the sugar were treated together, the sugar (ribose (Asp) was 7.5 mg / dL or more in the case of the composite form having the composition of glucose (Gluc) or glucose (Gluc)) of 2.6 to 7.75 g.

Test substance (g / dL) N PT aPTT TT Average Standard Deviation Average Standard Deviation Average Standard Deviation Control Purified water 3 0.00 0.00 0.00 0.00 0.00 0.00 Control Asp 7.5 mg / ml 3 26.02 1.41 29.82 1.78 23.95 2.18 Comparative Example 2-2 Mann 3.1 3 2.71 0.94 0.65 3.67 11.67 1.56 Mann 6.2 3 5.96 3.29 1.24 4.22 22.74 4.59 Mann 12.4 3 13.55 2.05 7.98 3.07 47.87 4.27 Fruc 6.2 3 0.54 0.94 -0.20 3.04 13.19 1.43 Fruc 12.4 3 0.54 0.94 0.58 4.29 30.07 1.65 Comparative Example 1-2 Tau 4.3 3 -3.79 2.35 -5.50 3.82 9.51 2.10 Comparative Example 2-4 Tau 4.3+ Mann 3.1 3 -1.08 2.35 -3.14 3.83 17.48 0.78 Tau 4.3+ Mann 7.75 3 6.23 1.69 -0.02 3.64 31.60 2.08 Tau 4.3+ Fruc 7.75 3 0.00 0.81 -3.49 2.86 30.39 2.81 Examples 1-2 TauAlc 4.3 3 -3.79 2.35 -5.45 2.18 10.12 0.78 Example
2-3 TauAlc 4.3+ Mann 3.1 3 0.54 1.88 -2.65 3.33 18.74 3.05 TauAlc 4.3+ Mann 7.75 2* 5.69 0.00 1.03 0.37 34.59 2.63 TauAlc 4.3+ Fruc 7.75 3 -1.36 0.47 -3.50 2.58 29.78 2.97

* Samples except for one sample showing extreme value

As shown in Table 20, the TT delay rate was increased when the modified taurine (TauAlc) was treated alone or in combination with the sugar, compared with the taurine (Tau). When the modified taurine (TauAlc) and the sugar were treated together, ) Or fructose (Fruc)) was 7.75 g, it was confirmed that TT delay was aspirin (Asp) of 7.5 mg / dL or more.

Antidiabetic and anti-obesity efficacy experiments

Experimental Method

An antidiabetic efficacy candidate was evaluated using a GTT (Glucose Tolerance Test) method, which is a representative diabetic diagnostic test method, on an 8-week-old male mouse (C57BL / 6) (available from Coatec).

The environmental conditions of the mice were set at 22 ± 2 ° C and relative humidity of 55 ~ 60%. The mice were lighted for 12 hours a day and exited for 12 hours. Five mice were assigned to each group, and the male mice were randomly divided into one group, each of which had a strong domain dispute.

Feeds were fed with water for 10 weeks (60% of calories from fat; research diet inc., New Brunswick, NJ) and water. At this time, the samples prepared in Examples 1-2 (3), 2-1, 2-4-1, 2-4-2 and 2-5 were mixed and supplied without limitation. Metformin (M-072, Sigma) (250 mg / kg) was used as a positive control and Comparative Examples 1-1, 2-3-2, 2-5-1, 2-5-2 and 2- -6 were used.

For reference, the samples prepared in Examples 2-4-1, 2-4-2 and 2-5 were set to the dose that adult male (60 kg) took for 3 days, and the dose of mice (12 times / kg, NIH guidance material) to produce animal samples. That is, the amount that an adult male (60 kg) takes for three days is 180 matched / kg, which is 15 matched / kg. Therefore, the average weight of the mouse is about 20 g, which corresponds to 750 matches / mouse (20 g). Thus, one mouse was allowed to take 1/750 of the prepared sample per day.

In addition, the samples prepared in Examples 1-2 (3) and 2-1 were set to an amount that would be taken by a 2-day adult male (60 kg), and the dose was taken (12 times / kg, see US NIH guidance data) ) To prepare an animal sample. That is, the amount that an adult male (60 kg) takes two days is 120 matched / kg, which is 10 matched / kg. Therefore, the average weight of the mouse is about 20 g, which corresponds to 500 matches / mouse (20 g). Thus, one mouse was allowed to take 1/500 of the prepared sample per day.

Dietary intake and body weight gain were monitored weekly for 8 weeks. Body weight and dietary dose were measured immediately before the first dose, followed by body weight and dietary dose at weekly intervals.

Glucose tolerance test (GTT) was performed at 8 weeks after high fat diet. The mouse was fasted for 8 hours before the experiment. After that, the blood was collected from the tail vein, and the initial blood glucose was measured with a glucose meter (AUTO-CHEK, Diatek Korea) and glucose was intraperitoneally administered at a concentration of 1 g / kg , Blood samples were collected at 30 minutes, 60 minutes, 90 minutes, and 120 minutes, and blood glucose was measured (an average of 5 mice per group).

The blood biochemical tests include insulin (AKRIN-011T, Shibayagi, Japan), glucose (AM202, Asan Pharmaceuticals, Korea), triglyceride (AM157, ASAN PHARMACEUTICALS), total cholesterol (AM202, AM101, manufactured by Asan Pharmaceutical Co., Ltd.) were analyzed using enzymatic assay kits.

The mice were sacrificed by cervical dislocation to obtain serum at 10 weeks of high fat diet. For histological examination, liver, white adipose tissue (WAT), brown adipose tissue (BAT) and kidney were fixed to formalin (50-00-0, Junsei, Japan), and remaining organs were stored at -70 ° C. The blood collected from the heart was coagulated to obtain serum, and stored at -70 ° C.

(MHS-16, Sigma-Aldrich, USA) and eosin (HT110116, Sigma-Aldrich, USA) were applied to paraffin blocks and fixed at 4% neutral buffered formalin for histological examination. ). After the tissue samples were prepared, they were mounted with glycerin gel mounting media (SP15-100, Fisher Scientific, USA), covered with cover glasses and observed with a microscope (IX71, OLYMPUS, Japan).

The results of the experiments were expressed as mean ± S.E.M., and significance between the experimental groups was evaluated at the level of * P <0.05 after statistical treatment using Student's T-Test.

Measurement result

(1) Results of measurement of weight gain

Weight, weight gain and weight gain T-test results are shown in Figs. 10-15 and Tables 21-38.

Weight (g) division Before administration 1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks 7 weeks 8 weeks Control Normal diet
(RD) Average 17.80 19.36 21.48 22.44 23.56 24.32 24.78 25.74 26.18 Deviation 0.17 0.35 0.54 0.56 0.54 0.57 0.66 0.78 0.81 Control Highland method
(HFD) Average 20.68 23.58 24.87 26.50 28.16 30.12 31.85 33.04 35.96 Deviation 0.29 0.54 0.53 0.57 0.62 0.68 0.52 0.47 0.42 Examples 1-2
(3) DT15
(TauAlc) Average 17.65 20.30 22.05 23.93 25.18 26.03 27.90 28.75 29.23 Deviation 0.16 0.17 0.27 0.26 0.27 0.22 0.41 0.38 0.37 Comparative Example 1-1 DT19
(Tau) Average 19.26 21.46 23.62 24.60 25.78 27.38 27.20 28.06 28.78 Deviation 0.28 0.35 0.59 0.66 0.63 0.77 0.84 0.97 1.10 Control Metformin
(MET) Average 19.30 21.00 22.78 23.84 25.18 25.72 26.34 27.52 28.20 Deviation 0.62 0.72 0.99 0.97 1.16 1.04 1.07 1.24 1.37

Weight gain (g) division 1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks 7 weeks 8 weeks Control Normal diet
(RD) Average 1.56 3.68 4.64 5.76 6.52 6.98 7.94 8.38 Deviation 0.24 0.45 0.48 0.44 0.51 0.59 0.68 0.73 Control Highland method
(HFD) Average 2.90 4.19 5.82 7.48 9.44 11.17 12.36 15.28 Deviation 0.52 0.50 0.51 0.49 0.52 0.36 0.35 0.29 Examples 1-2
(3) DT15
(TauAlc) Average 2.65 4.40 6.28 7.53 8.38 10.25 11.10 11.58 Deviation 0.25 0.28 0.34 0.40 0.36 0.52 0.46 0.40 Comparative Example 1-1 DT19
(Tau) Average 2.20 4.36 5.34 6.52 8.12 7.94 8.80 9.52 Deviation 0.10 0.73 0.81 0.74 0.91 0.91 1.06 1.12 Control Metformin
(MET) Average 1.70 3.48 4.54 5.88 6.42 7.04 8.22 8.90 Deviation 0.30 1.10 0.99 1.19 1.11 1.14 1.29 1.44

group 1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks 7 weeks 8 weeks HFD vs DT15 0.7736 0.8052 0.6050 0.9579 0.2443 0.1925 0.0656 0.0000 HFD vs DT19 0.3663 0.8499 0.6119 0.2908 0.1971 0.0016 0.0013 0.0000 DT15 vs. DT19 0.1145 0.9645 0.3648 0.3044 0.8198 0.0801 0.1116 0.1623

It can be seen from Tables 21 to 23 that both DT15 treated with modified taurine (TauAlc) and DT19 treated with taurine (Tau) showed significant weight gain compared with high fat diet (HFD) alone at 8 weeks after high fat diet (HFD) It was confirmed that it shows an increase inhibiting effect.

Weight (g) division Before administration 1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks 7 weeks 8 weeks Control Normal diet
(RD) Average 17.80 19.36 21.48 22.44 23.56 24.32 24.78 25.74 26.18 Deviation 0.17 0.35 0.54 0.56 0.54 0.57 0.66 0.78 0.81 Control Highland method
(HFD) Average 20.68 23.58 24.87 26.50 28.16 30.12 31.85 33.04 35.96 Deviation 0.29 0.54 0.53 0.57 0.62 0.68 0.52 0.47 0.42 Example 2-1 DT16
(TauAlc 8.6 + Ara 2.5) Average 19.88 22.16 23.94 25.02 26.44 27.34 27.92 28.50 30.62 Deviation 0.32 0.32 0.43 0.53 0.75 0.71 0.79 0.74 0.84 Comparative Example
2-3-2 DT 18
(Tau 8.6 + Ara 2.5) Average 20.20 22.29 23.47 25.17 26.70 27.67 29.03 30.77 32.03 Deviation 0.50 0.55 0.58 0.97 1.30 1.58 1.96 2.11 2.72 Control Metformin
(MET) Average 19.30 21.00 22.78 23.84 25.18 25.72 26.34 27.52 28.20 Deviation 0.62 0.72 0.99 0.97 1.16 1.04 1.07 1.24 1.37

Weight gain (g) division 1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks 7 weeks 8 weeks Control Normal diet
(RD) Average 1.56 3.68 4.64 5.76 6.52 6.98 7.94 8.38 Deviation 0.24 0.45 0.48 0.44 0.51 0.59 0.68 0.73 Control Highland method
(HFD) Average 2.90 4.19 5.82 7.48 9.44 11.17 12.36 15.28 Deviation 0.52 0.50 0.51 0.49 0.52 0.36 0.35 0.29 Example 2-1 DT16
(TauAlc 8.6 + Ara 2.5) Average 2.28 4.06 5.14 6.56 7.46 8.04 8.62 10.74 Deviation 0.29 0.71 0.75 1.00 1.00 1.05 1.02 1.15 Comparative Example
2-3-2 DT 18
(Tau 8.6 + Ara 2.5) Average 2.09 3.27 4.97 6.50 7.47 8.83 10.57 11.83 Deviation 0.16 0.91 1.42 1.77 2.02 2.40 2.54 3.15 Control Metformin
(MET) Average 1.70 3.48 4.54 5.88 6.42 7.04 8.22 8.90 Deviation 0.30 1.10 0.99 1.19 1.11 1.14 1.29 1.44

group 1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks 7 weeks 8 weeks HFD vs DT16 0.4351 0.8839 0.4636 0.3673 0.0722 0.0036 0.0008 0.0002 HFD vs DT18 0.4222 0.3970 0.4895 0.4556 0.1827 0.1121 0.2258 0.0582 DT16 vs DT18 0.6482 0.5201 0.9100 0.9753 0.9974 0.7355 0.4307 0.7065

It can be seen from the above Tables 24 to 26 that DT16 treated with modified taurine (TauAlc) and arabinose (Ara) showed significant weight gain inhibition effect compared to the high fat diet (HFD) alone at 8 weeks after high fat diet (HFD) , But it was confirmed that DT18 administered with taurine and arabinose (Ara) did not show a significant effect of inhibiting weight gain.

There was no statistically significant difference in the inhibition of weight gain between the DT16 and DT18 groups. However, DT16 was considered to be more effective in controlling weight than DT18 in comparison with HFD.

Weight (g) division Before administration 1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks 7 weeks 8 weeks Control Normal diet
(RD) Average 17.80 19.36 21.48 22.44 23.56 24.32 24.78 25.74 26.18 Deviation 0.17 0.35 0.54 0.56 0.54 0.57 0.66 0.78 0.81 Control Highland method
(HFD) Average 20.68 23.58 24.87 26.50 28.16 30.12 31.85 33.04 35.96 Deviation 0.29 0.54 0.53 0.57 0.62 0.68 0.52 0.47 0.42 Example 2-1 DT20
(TauAlc 8.6 + Xyl 3.5) Average 19.56 22.76 24.02 25.38 27.38 28.40 28.86 30.28 32.28 Deviation 0.49 0.67 0.48 0.76 0.77 0.88 1.05 0.94 0.96 Comparative Example
2-3-2 DT 21
(Tau 8.6 + Xyl 3.5) Average 19.64 21.64 24.22 26.16 27.28 27.22 29.04 30.02 31.74 Deviation 0.15 0.15 0.10 0.32 0.27 0.27 0.16 0.34 0.81 Control Metformin
(MET) Average 19.30 21.00 22.78 23.84 25.18 25.72 26.34 27.52 28.20 Deviation 0.62 0.72 0.99 0.97 1.16 1.04 1.07 1.24 1.37

Weight gain (g) division 1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks 7 weeks 8 weeks Control Normal diet
(RD) Average 1.56 3.68 4.64 5.76 6.52 6.98 7.94 8.38 Deviation 0.24 0.45 0.48 0.44 0.51 0.59 0.68 0.73 Control Highland method
(HFD) Average 2.90 4.19 5.82 7.48 9.44 11.17 12.36 15.28 Deviation 0.52 0.50 0.51 0.49 0.52 0.36 0.35 0.29 Example 2-1 DT20
(TauAlc 8.6 + Xyl 3.5) Average 3.20 4.46 5.82 7.82 8.84 9.30 10.72 12.72 Deviation 0.36 0.72 0.56 1.11 0.85 1.01 1.02 1.13 Comparative Example
2-3-2 DT 21
(Tau 8.6 + Xyl 3.5) Average 2.00 4.58 6.52 7.64 7.58 9.40 10.38 12.10 Deviation 0.14 0.14 0.41 0.41 0.32 0.27 0.41 0.95 Control Metformin
(MET) Average 1.70 3.48 4.54 5.88 6.42 7.04 8.22 8.90 Deviation 0.30 1.10 0.99 1.19 1.11 1.14 1.29 1.44

group 1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks 7 weeks 8 weeks HFD vs DT20 0.7082 0.7623 1.0000 0.7485 0.5373 0.0498 0.0774 0.0118 HFD vs DT21 0.2521 0.6032 0.3923 0.8377 0.0330 0.0072 0.0042 0.0012 DT20 vs. DT21 0.0154 0.8733 0.3409 0.8829 0.2028 0.9263 0.7659 0.6847

From Tables 27 to 29, DT20 to which modified taurine (TauAlc) and xylose (Ara) were administered and DT21 to which taurine (Tau) and xylose (Ara) It was confirmed that the high fat diet (HFD) alone had a significant weight gain inhibitory effect.

Weight (g) division Before administration 1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks 7 weeks 8 weeks Control Normal diet
(RD) Average 22.894 23.692 24.138 24.285 24.507 24.416 24.720 24.782 25.684 Deviation 0.599 0.363 0.442 0.283 0.183 0.221 0.321 0.362 0.170 Control Highland method
(HFD) Average 22.322 24.642 26.136 27.642 29.472 31.176 32.494 34.478 38.764 Deviation 0.666 0.741 0.754 0.775 0.945 0.938 0.803 1.344 1.468 Example
2-4-1 DT7 (TauAlc 8.6 + Cat 3 + Bet 4) Average 20.834 22.456 22.744 24.094 25.884 27.388 29.236 29.638 31.662 Deviation 0.660 0.542 0.519 0.545 0.701 0.934 1.114 1.383 1.727 Comparative Example
2-5-1 DT11
(Tau 8.6 + Cat 3 + Bet 4) Average 20.420 24.418 25.360 27.388 29.178 32.794 35.460 36.012 38.370 Deviation 0.353 0.498 0.608 0.630 0.853 0.843 1.101 0.950 0.771 Control Metformin
(MET) Average 21.105 23.550 23.608 25.125 25.705 27.198 28.355 27.368 29.343 Deviation 0.568 0.727 0.794 0.829 1.034 1.022 1.101 1.319 1.516

Weight gain (g) division 1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks 7 weeks 8 weeks Control Normal diet
(RD) Average 0.798 1.244 1.391 1.613 1.522 1.826 1.888 2.790 Deviation 0.444 0.473 0.475 0.448 0.507 0.504 0.499 0.517 Control Highland method
(HFD) Average 2.320 3.814 5.320 7.150 8.854 10.172 12.156 16.442 Deviation 0.351 0.518 0.458 0.601 0.899 0.737 1.438 1.296 Example
2-4-1 DT7 (TauAlc 8.6 + Cat 3 + Bet 4) Average 1.622 1.910 3.260 5.050 6.554 8.402 8.804 10.828 Deviation 0.251 0.200 0.259 0.269 0.334 0.486 0.733 1.120 Comparative Example
2-5-1 DT11
(Tau 8.6 + Cat 3 + Bet 4) Average 3.998 4.940 6.968 8.758 12.374 15.040 15.592 17.950 Deviation 0.605 0.789 0.869 1.066 1.017 1.162 1.013 0.583 Control Metformin
(MET) Average 2.445 2.503 4.020 4.600 6.093 7.250 6.263 8.238 Deviation 0.442 0.383 0.637 0.910 0.795 1.090 0.944 1.090

group 1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks 7 weeks 8 weeks HFD vs. DT7 0.1444 0.0090 0.0045 0.0128 0.0434 0.0799 0.0715 0.0112 HFD vs DT11 0.0433 0.2672 0.1320 0.2253 0.0320 0.0077 0.0865 0.3197 DT7 vs DT11 0.0067 0.0059 0.0035 0.0097 0.0006 0.0008 0.0006 0.0005

It can be seen from Tables 30 to 32 that DT7 administered with modified taurine (TauAlc), catechin (Cat) and betaine was significantly higher than that of high fat diet (HFD) alone at 8 weeks after high fat diet (HFD) And DT11, which was administered with taurine, catechin (Bet) and betaine (Bet), did not show significant weight gain inhibitory effect. In addition, DT7 administration group was significantly higher in weight control effect than DT11 administration group.

Weight (g) division Before administration 1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks 7 weeks 8 weeks Control Normal diet
(RD) Average 22.894 23.692 24.138 24.285 24.507 24.416 24.720 24.782 25.684 Deviation 0.599 0.363 0.442 0.283 0.183 0.221 0.321 0.362 0.170 Control Highland method
(HFD) Average 22.322 24.642 26.136 27.642 29.472 31.176 32.494 34.478 38.764 Deviation 0.666 0.741 0.754 0.775 0.945 0.938 0.803 1.344 1.468 Example
2-4-2 DT10 (TauAlc 8.6 + EGCG 1.5 + Bet 4) Average 21.956 25.356 25.458 25.998 27.062 29.836 31.732 30.562 32.740 Deviation 0.483 0.640 0.524 0.740 0.666 0.811 0.946 0.975 1.135 Comparative Example
2-5-2 DT14
(Tau 8.6 + EGCG 1.5 + Bet 4) Average 21.440 24.750 26.114 27.556 29.456 31.968 34.020 32.874 37.470 Deviation 0.638 0.998 1.142 1.400 1.654 2.005 2.181 2.012 2.186 Control Metformin
(MET) Average 21.105 23.550 23.608 25.125 25.705 27.198 28.355 27.368 29.343 Deviation 0.568 0.727 0.794 0.829 1.034 1.022 1.101 1.319 1.516

Weight gain (g) division 1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks 7 weeks 8 weeks Control Normal diet
(RD) Average 0.798 1.244 1.391 1.613 1.522 1.826 1.888 2.790 Deviation 0.444 0.473 0.475 0.448 0.507 0.504 0.499 0.517 Control Highland method
(HFD) Average 2.320 3.814 5.320 7.150 8.854 10.172 12.156 16.442 Deviation 0.351 0.518 0.458 0.601 0.899 0.737 1.438 1.296 Example
2-4-2 DT10 (TauAlc 8.6 + EGCG 1.5 + Bet 4) Average 3.400 3.502 4.042 5.106 7.880 9.776 8.606 10.784 Deviation 0.274 0.253 0.330 0.441 0.683 0.929 1.126 1.204 Comparative Example
2-5-2 DT14
(Tau 8.6 + EGCG 1.5 + Bet 4) Average 3.310 4.674 6.116 8.016 10.528 12.580 11.434 16.030 Deviation 0.407 0.580 0.850 1.077 1.412 1.596 1.414 1.577 Control Metformin
(MET) Average 2.445 2.503 4.020 4.600 6.093 7.250 6.263 8.238 Deviation 0.442 0.383 0.637 0.910 0.795 1.090 0.944 1.090

group 1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks 7 weeks 8 weeks HFD vs DT10 0.0416 0.6033 0.0536 0.0254 0.4134 0.7471 0.0879 0.0126 HFD vs DT14 0.1029 0.3012 0.4338 0.5024 0.3467 0.2079 0.7296 0.8451 DT10 vs DT14 0.8592 0.1013 0.0526 0.0369 0.1299 0.1673 0.1564 0.0295

It can be seen from Tables 33 to 35 that the DT10 treated with modified taurine (TauAlc), epigallocatechin gallate (EGCG) and betaine (Beta) had high-fat diet (HFD) alone for 8 weeks after high- (TG), epigallocatechin gallate (EGCG), and betaine (DT) did not show a significant weight gain inhibitory effect I could confirm. In addition, DT10 administration group had significantly higher weight control effect than DT14 administration group.

Weight (g) division Before administration 1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks 7 weeks 8 weeks Control Normal diet
(RD) Average 25.706 25.614 27.006 26.814 28.744 29.442 29.258 29.476 27.442 Deviation 0.940 0.698 0.939 0.789 0.843 0.828 1.037 0.813 0.838 Control Highland method
(HFD) Average 24.920 27.448 29.878 34.452 36.850 38.748 40.524 43.686 42.344 Deviation 0.547 0.453 0.635 0.725 0.523 0.548 0.941 1.164 0.591 Example
2-5 DT4
(TauAlc 8.6 + EGCG 1.5 + Bet 4 + Xyl 3.5) Average 25.422 27.170 30.180 32.488 33.968 35.218 36.214 38.048 36.188 Deviation 0.237 0.565 0.800 0.744 0.642 0.781 1.038 1.053 1.044 Comparative Example
2-6 DT6
(Tau 8.6 + EGCG 1.5 + Bet 4 + Xyl 3.5) Average 23.088 26.216 29.082 32.910 32.922 38.018 39.414 40.820 40.618 Deviation 0.690 1.032 1.372 2.118 1.931 2.000 1.890 2.036 1.784 Control Metformin
(MET) Average 23.938 25.094 26.344 27.430 27.708 28.572 28.772 28.468 27.608 Deviation 0.612 0.551 0.792 0.710 0.915 0.853 0.784 0.836 0.979

Weight gain (g) division 1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks 7 weeks 8 weeks Control Normal diet
(RD) Average -0.092 1.300 1.108 3.038 3.736 3.552 3.770 1.736 Deviation 0.325 0.259 0.270 0.414 0.339 0.389 0.333 0.369 Control Highland method
(HFD) Average 2.528 4.958 9.532 11.930 13.828 15.604 18.766 17.424 Deviation 0.326 0.461 0.473 0.440 0.960 1.156 1.228 0.689 Example
2-5 DT4
(TauAlc 8.6 + EGCG 1.5 + Bet 4 + Xyl 3.5) Average 1.748 4.758 7.066 8.546 9.796 10.792 12.626 10.766 Deviation 0.372 0.625 0.580 0.465 0.589 0.835 0.846 0.849 Comparative Example
2-6 DT6
(Tau 8.6 + EGCG 1.5 + Bet 4 + Xyl 3.5) Average 3.128 5.994 9.822 9.834 14.930 16.326 17.732 17.530 Deviation 0.619 0.933 1.724 1.487 1.526 1.382 1.553 1.357 Control Metformin
(MET) Average 1.156 2.406 3.492 3.770 4.634 4.834 4.530 3.670 Deviation 0.180 0.185 0.223 0.350 0.398 0.398 0.936 0.463

group 1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks 7 weeks 8 weeks HFD vs DT4 0.1538 0.8033 0.0109 0.0007 0.0072 0.0097 0.0034 0.0003 HFD vs DT6 0.4161 0.3485 0.8751 0.2135 0.5580 0.6992 0.6156 0.9462 DT4 vs DT6 0.0924 0.3030 0.1682 0.4324 0.0138 0.0090 0.0203 0.0029

It can be seen from Tables 36 to 38 that DT4 to which modified taurine (TauAlc), epigallocatechin gallate (EGCG), betaine (Bet) and xylose were administered, (TGF), epigallocatechin gallate (EGCG), betaine (Bet), and xylose (Xyl) were administered compared with the high fat diet (HFD) alone. One DT6 did not show significant weight gain inhibitory effect. In addition, DT4 administration group was significantly higher in weight control effect than DT6 administration group.

(2) Glucose Tolerance Test (GTT)

GTT measurement results and T-test results thereof are shown in Figs. 16 to 19 and Tables 39 to 46 below.

division Blood sugar (mg / dl) 0 minutes 30 minutes 60 minutes 90 minutes 120 minutes Control Normal diet
(RD) Average 123.60 328.60 324.00 235.60 151.20 Deviation 6.44 12.80 30.00 16.84 6.57 Control Highland method
(HFD) Average 188.70 479.70 461.60 458.40 250.10 Deviation 10.67 26.87 39.06 33.42 27.98 Examples 1-2
(3) DT15
(TauAlc) Average 121.25 335.25 295.25 193.75 126.25 Deviation 3.73 3.77 7.73 11.43 0.56 Comparative Example 1-1 DT19
(Tau) Average 111.80 298.00 295.60 189.40 119.00 Deviation 11.08 26.76 11.52 9.75 6.47 Control Metformin
(MET) Average 144.20 386.40 301.40 194.40 135.20 Deviation 15.92 17.73 24.43 21.21 17.23

group Before administration 30 minutes later 60 minutes 90 minutes 120 minutes HFD vs DT15 0.0023 0.0062 0.0224 0.0004 0.0182 HFD vs DT19 0.0006 0.0010 0.0119 0.0001 0.0065 DT15 vs. DT19 0.4936 0.2625 0.9822 0.7904 0.3569

From the above Tables 39 and 40, fasting blood glucose levels of DT15 administered with modified taurine (TauAlc) and DT19 administered with taurine (Tau) are all lower than those of mice given only high-fat diet (HFD) , Which is similar to that of normal mice.

As a result of GTT, DT15 and DT19 group mice showed significantly higher blood glucose control ability than HFD alone group, and DT15 and DT19 showed similar blood glucose control ability.

division Blood sugar (mg / dl) 0 minutes 30 minutes 60 minutes 90 minutes 120 minutes Control Normal diet
(RD) Average 123.60 328.60 324.00 235.60 151.20 Deviation 6.44 12.80 30.00 16.84 6.57 Control Highland method
(HFD) Average 188.70 479.70 461.60 458.40 250.10 Deviation 10.67 26.87 39.06 33.42 27.98 Example 2-1 DT16
(TauAlc 8.6 + Ara 2.5) Average 117.00 289.20 302.20 196.20 121.40 Deviation 4.86 20.15 35.60 31.33 14.44 Comparative Example
2-3-2 DT 18
(Tau 8.6 + Ara 2.5) Average 169.33 367.00 343.00 236.33 172.67 Deviation 9.21 22.27 32.94 28.55 23.62 Control Metformin
(MET) Average 144.20 386.40 301.40 194.40 135.20 Deviation 15.92 17.73 24.43 21.21 17.23

group Before administration 30 minutes later 60 minutes 90 minutes 120 minutes HFD vs DT16 0.0005 0.0005 0.0219 0.0003 0.0084 HFD vs DT18 0.3740 0.0549 0.1488 0.0060 0.1848 DT16 vs DT18 0.0029 0.0626 0.4990 0.4502 0.1322

It can be seen from Tables 41 and 42 that fasting blood glucose levels of DT16 administered with modified taurine (TauAlc) and arabinose (Ara) are significantly lower than those of mice given only high-fat diet (HFD) , Which is the same level as that of normal mice.

As a result of GTT, DT16 mice showed significantly better blood glucose control ability than HFD alone and maintained blood glucose level in normal mouse. DT16 and DT18 administration groups were more effective than DT18 administration group And the fasting blood glucose level was significantly lower than the control group.

division Blood sugar (mg / dl) 0 minutes 30 minutes 60 minutes 90 minutes 120 minutes Control Normal diet
(RD) Average 123.60 328.60 324.00 235.60 151.20 Deviation 6.44 12.80 30.00 16.84 6.57 Control Highland method
(HFD) Average 188.70 479.70 461.60 458.40 250.10 Deviation 10.67 26.87 39.06 33.42 27.98 Example 2-1 DT20
(TauAlc 8.6 + Xyl 3.5) Average 115.00 306.40 330.40 240.40 142.80 Deviation 7.00 33.04 35.07 32.68 15.94 Comparative Example
2-3-2 DT 21
(Tau 8.6 + Xyl 3.5) Average 134.20 340.60 331.40 240.40 155.40 Deviation 13.04 27.41 29.45 35.59 19.60 Control Metformin
(MET) Average 144.20 386.40 301.40 194.40 135.20 Deviation 15.92 17.73 24.43 21.21 17.23

group Before administration 30 minutes later 60 minutes 90 minutes 120 minutes HFD vs DT20 0.0005 0.0019 0.0513 0.0012 0.0233 HFD vs DT21 0.0089 0.0065 0.0483 0.0014 0.0440 DT20 vs. DT21 0.2306 0.4486 0.9831 1.0000 0.6314

From the above Tables 43 and 44, it can be seen that fasting glucose (HFD) in fasting glucose of DT20 treated with modified taurine (TauAlc) and xylose (Ara) and DT21 administered with taurine (Tau) and xylose Compared with the control group, and it was confirmed that the level was similar to that of normal mice.

GTT results showed that both DT20 and DT21 mice showed significantly better blood glucose control than HFD alone and showed no significant difference between DT20 and DT21 but showed better efficacy than DT20 .

division Blood sugar (mg / dl) 0 minutes 30 minutes 60 minutes 90 minutes 120 minutes Control Normal diet
(RD) Average 120.60 392.80 296.00 203.20 158.60 Deviation 2.16 58.61 40.72 27.48 17.28 Control Highland method
(HFD) Average 210.80 528.20 527.40 448.80 342.20 Deviation 13.79 23.68 17.28 37.78 44.72 Example
2-5 DT4
(TauAlc 8.6 + EGCG 1.5 + Bet 4 + Xyl 3.5) Average 121.20 418.75 347.25 265.25 182.75 Deviation 7.81 25.89 10.69 25.07 9.81 Comparative Example
2-6 DT6
(Tau 8.6 + EGCG 1.5 + Bet 4 + Xyl 3.5) Average 199.60 505.80 471.40 417.40 318.40 Deviation 13.55 33.81 65.31 75.23 61.39 Control Metformin
(MET) Average 104.40 438.40 296.40 178.00 146.20 Deviation 3.72 8.68 23.15 14.35 3.02

group Before administration 30 minutes later After 60 minutes After 90 minutes After 120 minutes HFD vs DT4 0.0005 0.0211 0.0001 0.0075 0.0176 HFD vs DT6 0.5783 0.6021 0.4312 0.7189 0.7620 DT4 vs DT6 0.0010 0.1003 0.1409 0.1303 0.0949

From the above Tables 45 and 46, fasting blood glucose levels of DT4 treated with modified taurine (TauAlc), epigallocatechin gallate (EGCG), betaine (Bet) and xylose (Xyl) Compared with the control group, and it was confirmed that the level was similar to that of normal mice.

As a result of GTT, DT4 - treated mice were significantly superior to HFD - treated mice, but DT6 - treated mice showed lower blood glucose control ability.

(3) Blood biochemical test results

The results of the AST and ALT tests and the T-test results thereof are shown in Tables 47 to 56 below.

group Triglyceride
(Mg / dl) AST
(IU / L) ALT
(IU / L) Control The formula (RD) Average 76.02 91.34 10.85 Standard Deviation 14.42 7.23 6.20 Control Highlander (HFD) Average 148.78 129.70 24.71 Standard Deviation 32.47 6.48 3.75 Control Metformin (MET) Average 62.99 110.32 22.80 Standard Deviation 10.70 16.00 7.16 Examples 1-2
(3) DT15
(TauAlc) Average 53.62 98.96 14.02 Standard Deviation 7.22 6.11 3.82 Comparative Example 1-1 DT19
(Tau) Average 116.20 118.63 25.47 Standard Deviation 13.34 12.02 8.60

group Triglyceride AST ALT HFD vs DT15 0.0383 0.0118 0.0890 HFD vs DT19 0.3805 0.4408 0.9372 DT15 vs. DT19 0.0066 0.2211 0.3034

As shown in Tables 47 and 48 above, DT15 (modified taurine) shows similar or better levels of triglyceride, AST and ALT levels than normal mice, and significantly lower triglyceride levels than DT19 (taurine) AST and ALT levels were also low.

group Triglyceride
(Mg / dl) AST
(IU / L) ALT
(IU / L) Control The formula (RD) Average 76.02 91.34 10.85 Standard Deviation 14.42 7.23 6.20 Control Highlander (HFD) Average 148.78 129.70 24.71 Standard Deviation 32.47 6.48 3.75 Control Metformin
(MET) Average 62.99 110.32 22.80 Standard Deviation 10.70 16.00 7.16 Example 2-1 DT16
(TauAlc 8.6 + Ara 2.5) Average 54.30 96.48 10.68 Standard Deviation 8.66 3.52 4.15 Comparative Example
2-3-2 DT 18
(Tau 8.6 + Ara 2.5) Average 66.97 94.51 7.02 Standard Deviation 18.17 3.02 7.09

group Triglyceride AST ALT HFD vs DT16 0.0402 0.0042 0.0407 HFD vs DT18 0.1208 0.0076 0.0492 DT16 vs DT18 0.5202 0.7015 0.6546

As shown in Tables 49 and 50, DT16 (modified taurine + arabinose) and DT18 (taurine + arabinose) show AST and ALT levels similar to those of the normal formula (RD) HFD) than AST and ALT. In addition, DT16 showed lower levels of triglyceride than the normal diet (RD).

group Triglyceride
(Mg / dl) AST
(IU / L) ALT
(IU / L) Control The formula (RD) Average 76.02 91.34 10.85 Standard Deviation 14.42 7.23 6.20 Control Highlander (HFD) Average 148.78 129.70 24.71 Standard Deviation 32.47 6.48 3.75 Control Metformin
(MET) Average 62.99 110.32 22.80 Standard Deviation 10.70 16.00 7.16 Example 2-1 DT20
(TauAlc 8.6 + Xyl 3.5) Average 60.81 100.44 8.67 Standard Deviation 23.96 8.57 3.04 Comparative Example
2-3-2 DT 21
(Tau 8.6 + Xyl 3.5) Average 42.35 85.41 6.76 Standard Deviation 5.26 2.97 0.71

group Triglyceride AST ALT HFD vs DT20 0.0609 0.0261 0.0105 HFD vs DT21 0.0120 0.0003 0.0015 DT20 vs. DT21 0.4732 0.1363 0.5582

As shown in Tables 51 and 52, DT20 (modified taurine + xylose) and DT18 (taurine + xylose) show AST and ALT levels similar to those of the normal formula (RD) HFD) than AST and ALT. In addition, DT20 and DT21 showed lower levels of triglyceride than the normal diet (RD).

group Triglyceride AST
(IU / L) ALT
(IU / L) Control The formula (RD) Average 113.61 10.30 5.32 Standard Deviation 22.21 1.41 0.33 Control Highlander (HFD) Average 135.37 21.60 13.31 Standard Deviation 22.74 4.33 3.96 Control Metformin
(MET) Average 107.14 16.06 8.05 Standard Deviation 10.29 0.99 0.72 Example
2-4-1 DT7
(TauAlc 8.6 + Cat 3 + Bet 4) Average 100.68 11.41 7.01 Standard Deviation 7.23 1.71 1.07

group Triglyceride AST ALT HFD vs. DT7 0.451 0.071 0.176

As shown in Tables 53 and 54, DT7 (denatured taurine + catechin + betaine) showed similar levels of AST and ALT as that of the normal formula (RD) Respectively. In addition, DT7 showed lower triglyceride levels than the normal diet (RD).

group Triglyceride AST
(IU / L) ALT
(IU / L) Control The formula (RD) Average 81.39 10.09 0.99 Standard Deviation 17.61 3.35 0.38 Control Highlander (HFD) Average 133.80 26.92 14.79 Standard Deviation 8.13 4.44 5.31 Control Metformin (MET) Average 46.75 14.10 3.50 Standard Deviation 16.82 5.08 1.20 Example
2-5 DT4
(TauAlc 8.6 + EGCG 1.5 + Bet 4 + Xyl 3.5) Average 59.85 13.52 1.03 Standard Deviation 7.61 2.66 0.43 Comparative Example
2-6 DT6
(Tau 8.6 + EGCG 1.5 + Bet 4 + Xyl 3.5) Average 86.72 14.10 11.22 Standard Deviation 17.42 5.08 4.19

group Triglyceride AST ALT HFD vs DT4 0.003 0.0465 0.0565 HFD vs DT6 0.0386 0.0940 0.6119 DT4 vs DT6 0.2458 0.9284 0.0695

As shown in Tables 55 and 56 above, DT4 (denatured taurine + EGCG + betaine + xylose) shows AST and ALT levels similar to that of the normal formula (RD) ALT, respectively. In addition, DT4 showed lower levels of triglyceride than the normal diet (RD).

(4) Histological examination results

Examination results of liver, white adipose tissue (WAT), brown adipose tissue (BAT) and kidney tissue of experimental mice are shown in FIGS. 20 to 23.

20, in the high fat diet (HFD), fat cells were enlarged, fat accumulation was increased in brown adipose tissue, and fatty liver was severe. However, DT15 (metamorphine taurine) Showed a similar degree of fat cell size, decreased accumulation of fat in brown adipose tissue, decreased the incidence of fatty liver, and showed no renal toxicity.

21, in the high fat diet (HFD), fat cells were enlarged, fat accumulation was increased in brown adipose tissue, and fatty liver was severe, whereas DT16 (degenerated taurine + arabinose) , The accumulation of fat was decreased, the incidence of fatty liver was decreased, and kidney toxicity was not observed.

From FIG. 22, it can be seen that in the high fat diet (HFD), the size of the adipocytes is enlarged, the fat accumulation in the brown adipose tissue is greatly increased, the size of the glomeruli is increased, Catechin + betaine) decreased fat cell size, reduced fat accumulation in brown adipose tissue, inhibited the increase of glomerular size, decreased the incidence of fatty liver, and did not show renal toxicity.

23, in the high fat diet (HFD), the accumulation of macrophages between the size of adipocytes and adipocytes was increased, the fat was increased in the brown adipose tissue, the size of the glomeruli was increased, , DT4 (denatured taurine + EGCG + betaine + xylose) showed a partial increase in fat size but no accumulation of macrophages, decreased accumulation of fat in brown adipose tissue, inhibition of glomerular size increase, , And kidney toxicity was not observed.

While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereto will be. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (8)

A crystalline form of modified taurine obtained by dissolving taurine in water, adding alcohol and mixing, removing the water and alcohol, and recrystallizing the modified taurine,
The interatomic distance of the crystalline form of the modified taurine is such that the distance between the atoms of carbon (C) and sulfur (S) is 1.7730 to 1.7779 (Å) and the average distance between atoms of sulfur (S) And the maximum distance between atoms of sulfur (S) and three oxygen atoms (O) is 1.458 to 1.468 (A)
The crystal form of the modified taurine is a monoclinic crystal system in the X-ray single crystal analysis, a unit cell parameter (unit cell dimension) measured at a temperature of 100K and a space group of P2 (1) / c, (2)?, And? = 90, wherein a = 5.2607 (2)?, B = 11.6303 (4)?, C = 7.7903
Crystalline form of modified taurine.
The method according to claim 1,
The crystalline form of the modified taurine has a ratio of 891/847 absorption band intensity, 1182/1256 absorption band intensity ratio, and 1427/1458 absorption band intensity ratio at positions 847, 891, 1182, 1256, 1427, and 1458 cm ^-1 on Raman spectrum, &Lt; / RTI &gt; of the modified taurine.
The method according to claim 1,
Characterized in that the crystalline form of the modified taurine has an onset point at which the melting starts from 330 to 340 ° C.
The method according to claim 1,
Wherein the crystalline form of the modified taurine has a water solubility of 75 to 79 g / L.
The method according to claim 1,
Wherein the crystalline form of the modified taurine has a maximum density of 1.74 to 1.76 g / cm &lt; 3 &gt;.
delete (a) dissolving taurine in water;
(b) mixing taurine, water, and alcohol by adding an alcohol to the above (a); And
(c) recrystallizing the denatured taurine by removing water and an alcohol in the step (b)
Wherein an interatomic distance between the atoms of carbon (C) and sulfur (S) is 1.7730 to 1.7779 (Å), and an average distance between atoms of sulfur (S) and three oxygen (O) is 1.452 to 1.462 (Å), and the maximum distance between the atoms of sulfur (S) and oxygen (O) is 1.458 to 1.468 (Å)
The crystal form of the modified taurine is a monoclinic crystal system in the X-ray single crystal analysis, a unit cell parameter (unit cell dimension) measured at a temperature of 100K and a space group of P2 (1) / c, (2)?, And? = 90, wherein a = 5.2607 (2)?, B = 11.6303 (4)?, C = 7.7903
Method for the preparation of crystalline forms of modified taurine.
8. The method of claim 7,
Wherein the water in step (a) is used at 1 to 20 times the amount of water corresponding to a saturated aqueous taurine solution.

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